ID SETD2_HUMAN Reviewed; 2564 AA. AC Q9BYW2; O75397; O75405; Q17RW8; Q5BKS9; Q5QGN2; Q69YI5; Q6IN64; Q6ZN53; AC Q6ZS25; Q8N3R0; Q8TCN0; Q9C0D1; Q9H696; Q9NZW9; DT 17-OCT-2006, integrated into UniProtKB/Swiss-Prot. DT 18-MAY-2010, sequence version 3. DT 27-MAR-2024, entry version 192. DE RecName: Full=Histone-lysine N-methyltransferase SETD2 {ECO:0000305}; DE EC=2.1.1.359 {ECO:0000269|PubMed:19332550, ECO:0000269|PubMed:23043551, ECO:0000269|PubMed:27474439}; DE AltName: Full=HIF-1; DE AltName: Full=Huntingtin yeast partner B {ECO:0000303|PubMed:16118227}; DE AltName: Full=Huntingtin-interacting protein 1; DE Short=HIP-1; DE AltName: Full=Huntingtin-interacting protein B {ECO:0000303|PubMed:16118227}; DE AltName: Full=Lysine N-methyltransferase 3A {ECO:0000303|PubMed:19332550}; DE AltName: Full=Protein-lysine N-methyltransferase SETD2 {ECO:0000305}; DE EC=2.1.1.- {ECO:0000269|PubMed:27518565, ECO:0000269|PubMed:28753426}; DE AltName: Full=SET domain-containing protein 2 {ECO:0000303|PubMed:19332550}; DE Short=hSET2 {ECO:0000303|PubMed:19332550}; DE AltName: Full=p231HBP {ECO:0000303|PubMed:11461154}; GN Name=SETD2; GN Synonyms=HIF1, HYPB {ECO:0000303|PubMed:16118227}, KIAA1732 GN {ECO:0000303|PubMed:11214970}, KMT3A {ECO:0000303|PubMed:19332550}, GN SET2 {ECO:0000303|PubMed:19332550, ECO:0000303|Ref.7}; GN ORFNames=HSPC069; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16641997; DOI=10.1038/nature04728; RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J., RA Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P., RA Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A., RA Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L., RA Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G., RA Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W., RA Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., RA Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P., RA Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H., RA Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J., RA Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W., RA Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B., RA Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O., RA Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B., RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H., RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J., RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X., RA Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R., RA Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.; RT "The DNA sequence, annotation and analysis of human chromosome 3."; RL Nature 440:1194-1198(2006). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-1390. RC TISSUE=Brain, and Cerebellum; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 284-2564 (ISOFORM 3), NUCLEOTIDE RP SEQUENCE [LARGE SCALE MRNA] OF 927-1482 (ISOFORMS 1/2/3), AND NUCLEOTIDE RP SEQUENCE [LARGE SCALE MRNA] OF 2228-2564 (ISOFORM 1). RC TISSUE=Adipose tissue; RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [4] RP NUCLEOTIDE SEQUENCE [MRNA] OF 368-2564 (ISOFORM 1), FUNCTION (MICROBIAL RP INFECTION), DNA-BINDING, TISSUE SPECIFICITY, AND INTERACTION WITH HTT. RX PubMed=11461154; DOI=10.1006/mcne.2001.1004; RA Rega S., Stiewe T., Chang D.-I., Pollmeier B., Esche H., Bardenheuer W., RA Marquitan G., Puetzer B.M.; RT "Identification of the full-length huntingtin-interacting protein RT p231HBP/HYPB as a DNA-binding factor."; RL Mol. Cell. Neurosci. 18:68-79(2001). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 388-2564 (ISOFORM 1), AND VARIANT RP LEU-1962. RC TISSUE=Cerebellum, Duodenum, and Testis; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [MRNA] OF 481-2564 (ISOFORM 1), FUNCTION, RP AUTOMETHYLATION, MUTAGENESIS OF ARG-1625, AND INTERACTION WITH POLR2A. RX PubMed=16118227; DOI=10.1074/jbc.m504012200; RA Sun X.-J., Wei J., Wu X.-Y., Hu M., Wang L., Wang H.-H., Zhang Q.-H., RA Chen S.-J., Huang Q.-H., Chen Z.; RT "Identification and characterization of a novel human histone H3 lysine 36 RT specific methyltransferase."; RL J. Biol. Chem. 280:35261-35271(2005). RN [7] RP NUCLEOTIDE SEQUENCE [MRNA] OF 481-2564 (ISOFORM 2). RA Sun X.J., Wei J., Wu X.Y., Hu M., Wang H.H., Zhang Q.H., Huang Q.H., RA Chen Z.; RT "Identification of a human histone H3-K36-specific methyltransferase that RT is orthologous to Saccharomyces cerevisiae SET2 protein."; RL Submitted (MAR-2004) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 650-2564 (ISOFORM 1), AND VARIANT RP LEU-1962. RC TISSUE=Brain; RX PubMed=11214970; DOI=10.1093/dnares/7.6.347; RA Nagase T., Kikuno R., Hattori A., Kondo Y., Okumura K., Ohara O.; RT "Prediction of the coding sequences of unidentified human genes. XIX. The RT complete sequences of 100 new cDNA clones from brain which code for large RT proteins in vitro."; RL DNA Res. 7:347-355(2000). RN [9] RP SEQUENCE REVISION. RX PubMed=12168954; DOI=10.1093/dnares/9.3.99; RA Nakajima D., Okazaki N., Yamakawa H., Kikuno R., Ohara O., Nagase T.; RT "Construction of expression-ready cDNA clones for KIAA genes: manual RT curation of 330 KIAA cDNA clones."; RL DNA Res. 9:99-106(2002). RN [10] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1402-2069. RC TISSUE=Umbilical cord blood; RX PubMed=11042152; DOI=10.1101/gr.140200; RA Zhang Q.-H., Ye M., Wu X.-Y., Ren S.-X., Zhao M., Zhao C.-J., Fu G., RA Shen Y., Fan H.-Y., Lu G., Zhong M., Xu X.-R., Han Z.-G., Zhang J.-W., RA Tao J., Huang Q.-H., Zhou J., Hu G.-X., Gu J., Chen S.-J., Chen Z.; RT "Cloning and functional analysis of cDNAs with open reading frames for 300 RT previously undefined genes expressed in CD34+ hematopoietic stem/progenitor RT cells."; RL Genome Res. 10:1546-1560(2000). RN [11] RP NUCLEOTIDE SEQUENCE [MRNA] OF 2378-2564, AND INTERACTION WITH HTT. RC TISSUE=Frontal cortex; RX PubMed=9700202; DOI=10.1093/hmg/7.9.1463; RA Faber P.W., Barnes G.T., Srinidhi J., Chen J., Gusella J.F., RA MacDonald M.E.; RT "Huntingtin interacts with a family of WW domain proteins."; RL Hum. Mol. Genet. 7:1463-1474(1998). RN [12] RP INTERACTION WITH HTT. RX PubMed=10958656; DOI=10.1093/hmg/9.14.2175; RA Passani L.A., Bedford M.T., Faber P.W., McGinnis K.M., Sharp A.H., RA Gusella J.F., Vonsattel J.-P., MacDonald M.E.; RT "Huntingtin's WW domain partners in Huntington's disease post-mortem brain RT fulfill genetic criteria for direct involvement in Huntington's disease RT pathogenesis."; RL Hum. Mol. Genet. 9:2175-2182(2000). RN [13] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026; RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.; RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling RT networks."; RL Cell 127:635-648(2006). RN [14] RP INTERACTION WITH TP53. RX PubMed=18585004; DOI=10.1016/j.cellsig.2008.05.012; RA Xie P., Tian C., An L., Nie J., Lu K., Xing G., Zhang L., He F.; RT "Histone methyltransferase protein SETD2 interacts with p53 and selectively RT regulates its downstream genes."; RL Cell. Signal. 20:1671-1678(2008). RN [15] RP FUNCTION, AND INTERACTION WITH IWS1. RX PubMed=19141475; DOI=10.1101/gad.1720008; RA Yoh S.M., Lucas J.S., Jones K.A.; RT "The Iws1:Spt6:CTD complex controls cotranscriptional mRNA biosynthesis and RT HYPB/Setd2-mediated histone H3K36 methylation."; RL Genes Dev. 22:3422-3434(2008). RN [16] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1228, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18220336; DOI=10.1021/pr0705441; RA Cantin G.T., Yi W., Lu B., Park S.K., Xu T., Lee J.-D., Yates J.R. III; RT "Combining protein-based IMAC, peptide-based IMAC, and MudPIT for efficient RT phosphoproteomic analysis."; RL J. Proteome Res. 7:1346-1351(2008). RN [17] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-321; SER-323; SER-624; RP SER-754; SER-1228; THR-1872; SER-2080 AND SER-2082, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=18669648; DOI=10.1073/pnas.0805139105; RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., RA Elledge S.J., Gygi S.P.; RT "A quantitative atlas of mitotic phosphorylation."; RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008). RN [18] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=19413330; DOI=10.1021/ac9004309; RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.; RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a RT refined SCX-based approach."; RL Anal. Chem. 81:4493-4501(2009). RN [19] RP FUNCTION, CATALYTIC ACTIVITY, AND INTERACTION WITH HNRNPL. RX PubMed=19332550; DOI=10.1074/jbc.m808431200; RA Yuan W., Xie J., Long C., Erdjument-Bromage H., Ding X., Zheng Y., RA Tempst P., Chen S., Zhu B., Reinberg D.; RT "Heterogeneous nuclear ribonucleoprotein L is a subunit of human KMT3a/Set2 RT complex required for H3 Lys-36 trimethylation activity in vivo."; RL J. Biol. Chem. 284:15701-15707(2009). RN [20] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-131; SER-321; SER-323; RP SER-708; SER-744 AND SER-754, AND IDENTIFICATION BY MASS SPECTROMETRY RP [LARGE SCALE ANALYSIS]. RC TISSUE=Leukemic T-cell; RX PubMed=19690332; DOI=10.1126/scisignal.2000007; RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., RA Rodionov V., Han D.K.; RT "Quantitative phosphoproteomic analysis of T cell receptor signaling RT reveals system-wide modulation of protein-protein interactions."; RL Sci. Signal. 2:RA46-RA46(2009). RN [21] RP INVOLVEMENT IN RCC. RX PubMed=20054297; DOI=10.1038/nature08672; RA Dalgliesh G.L., Furge K., Greenman C., Chen L., Bignell G., Butler A., RA Davies H., Edkins S., Hardy C., Latimer C., Teague J., Andrews J., RA Barthorpe S., Beare D., Buck G., Campbell P.J., Forbes S., Jia M., RA Jones D., Knott H., Kok C.Y., Lau K.W., Leroy C., Lin M.L., McBride D.J., RA Maddison M., Maguire S., McLay K., Menzies A., Mironenko T., Mulderrig L., RA Mudie L., O'Meara S., Pleasance E., Rajasingham A., Shepherd R., Smith R., RA Stebbings L., Stephens P., Tang G., Tarpey P.S., Turrell K., Dykema K.J., RA Khoo S.K., Petillo D., Wondergem B., Anema J., Kahnoski R.J., Teh B.T., RA Stratton M.R., Futreal P.A.; RT "Systematic sequencing of renal carcinoma reveals inactivation of histone RT modifying genes."; RL Nature 463:360-363(2010). RN [22] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-321; SER-323; SER-624 AND RP THR-1872, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [23] RP FUNCTION. RX PubMed=21792193; DOI=10.1038/nsmb.2123; RA de Almeida S.F., Grosso A.R., Koch F., Fenouil R., Carvalho S., Andrade J., RA Levezinho H., Gut M., Eick D., Gut I., Andrau J.C., Ferrier P., RA Carmo-Fonseca M.; RT "Splicing enhances recruitment of methyltransferase HYPB/Setd2 and RT methylation of histone H3 Lys36."; RL Nat. Struct. Mol. Biol. 18:977-983(2011). RN [24] RP FUNCTION. RX PubMed=21526191; DOI=10.1371/journal.pone.0018844; RA Hahn M.A., Wu X., Li A.X., Hahn T., Pfeifer G.P.; RT "Relationship between gene body DNA methylation and intragenic H3K9me3 and RT H3K36me3 chromatin marks."; RL PLoS ONE 6:E18844-E18844(2011). RN [25] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-321; SER-323; SER-624; RP SER-754 AND SER-2082, AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE RP ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [26] RP INVOLVEMENT IN LLS. RX PubMed=23160955; DOI=10.1126/science.1227764; RA O'Roak B.J., Vives L., Fu W., Egertson J.D., Stanaway I.B., Phelps I.G., RA Carvill G., Kumar A., Lee C., Ankenman K., Munson J., Hiatt J.B., RA Turner E.H., Levy R., O'Day D.R., Krumm N., Coe B.P., Martin B.K., RA Borenstein E., Nickerson D.A., Mefford H.C., Doherty D., Akey J.M., RA Bernier R., Eichler E.E., Shendure J.; RT "Multiplex targeted sequencing identifies recurrently mutated genes in RT autism spectrum disorders."; RL Science 338:1619-1622(2012). RN [27] RP FUNCTION, INVOLVEMENT IN RCC, VARIANTS RCC ASP-1733 AND PRO-1769, AND RP CHARACTERIZATION OF VARIANTS RCC ASP-1733 AND PRO-1769. RX PubMed=23622243; DOI=10.1016/j.cell.2013.03.025; RA Li F., Mao G., Tong D., Huang J., Gu L., Yang W., Li G.M.; RT "The histone mark H3K36me3 regulates human DNA mismatch repair through its RT interaction with MutSalpha."; RL Cell 153:590-600(2013). RN [28] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-131; SER-344; SER-422; RP SER-532; SER-614; SER-624; THR-626; SER-744; SER-754; SER-1098; SER-1228; RP SER-1696; THR-1853; THR-1872; SER-1888; SER-1952; SER-2080 AND SER-2082, RP AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma, and Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [29] RP INVOLVEMENT IN RCC. RX PubMed=23792563; DOI=10.1038/nature12222; RA Creighton C.J., Morgan M., Gunaratne P.H., Wheeler D.A., Gibbs R.A., RA Gordon Robertson A., Chu A., Beroukhim R., Cibulskis K., Signoretti S., RA Vandin Hsin-Ta Wu F., Raphael B.J., Verhaak R.G., Tamboli P., RA Torres-Garcia W., Akbani R., Weinstein J.N., Reuter V., Hsieh J.J., RA Rose Brannon A., Ari Hakimi A., Jacobsen A., Ciriello G., Reva B., RA Ricketts C.J., Marston Linehan W., Stuart J.M., Kimryn Rathmell W., RA Shen H., Laird P.W., Muzny D., Davis C., Morgan M., Xi L., Chang K., RA Kakkar N., Trevino L.R., Benton S., Reid J.G., Morton D., Doddapaneni H., RA Han Y., Lewis L., Dinh H., Kovar C., Zhu Y., Santibanez J., Wang M., RA Hale W., Kalra D., Creighton C.J., Wheeler D.A., Gibbs R.A., Getz G., RA Cibulskis K., Lawrence M.S., Sougnez C., Carter S.L., Sivachenko A., RA Lichtenstein L., Stewart C., Voet D., Fisher S., Gabriel S.B., Lander E., RA Beroukhim R., Schumacher S.E., Tabak B., Saksena G., Onofrio R.C., RA Carter S.L., Cherniack A.D., Gentry J., Ardlie K., Sougnez C., Getz G., RA Gabriel S.B., Meyerson M., Gordon Robertson A., Chu A., Chun H.J., RA Mungall A.J., Sipahimalani P., Stoll D., Ally A., Balasundaram M., RA Butterfield Y.S., Carlsen R., Carter C., Chuah E., Coope R.J., Dhalla N., RA Gorski S., Guin R., Hirst C., Hirst M., Holt R.A., Lebovitz C., Lee D., RA Li H.I., Mayo M., Moore R.A., Pleasance E., Plettner P., Schein J.E., RA Shafiei A., Slobodan J.R., Tam A., Thiessen N., Varhol R.J., Wye N., RA Zhao Y., Birol I., Jones S.J., Marra M.A., Auman J.T., Tan D., Jones C.D., RA Hoadley K.A., Mieczkowski P.A., Mose L.E., Jefferys S.R., Topal M.D., RA Liquori C., Turman Y.J., Shi Y., Waring S., Buda E., Walsh J., Wu J., RA Bodenheimer T., Hoyle A.P., Simons J.V., Soloway M.G., Balu S., RA Parker J.S., Neil Hayes D., Perou C.M., Kucherlapati R., Park P., Shen H., RA Triche T. Jr., Weisenberger D.J., Lai P.H., Bootwalla M.S., Maglinte D.T., RA Mahurkar S., Berman B.P., Van Den Berg D.J., Cope L., Baylin S.B., RA Laird P.W., Creighton C.J., Wheeler D.A., Getz G., Noble M.S., Dicara D., RA Zhang H., Cho J., Heiman D.I., Gehlenborg N., Voet D., Mallard W., Lin P., RA Frazer S., Stojanov P., Liu Y., Zhou L., Kim J., Lawrence M.S., Chin L., RA Vandin F., Wu H.T., Raphael B.J., Benz C., Yau C., Reynolds S.M., RA Shmulevich I., Verhaak R.G., Torres-Garcia W., Vegesna R., Kim H., RA Zhang W., Cogdell D., Jonasch E., Ding Z., Lu Y., Akbani R., Zhang N., RA Unruh A.K., Casasent T.D., Wakefield C., Tsavachidou D., Chin L., RA Mills G.B., Weinstein J.N., Jacobsen A., Rose Brannon A., Ciriello G., RA Schultz N., Ari Hakimi A., Reva B., Antipin Y., Gao J., Cerami E., RA Gross B., Arman Aksoy B., Sinha R., Weinhold N., Onur Sumer S., RA Taylor B.S., Shen R., Ostrovnaya I., Hsieh J.J., Berger M.F., Ladanyi M., RA Sander C., Fei S.S., Stout A., Spellman P.T., Rubin D.L., Liu T.T., RA Stuart J.M., Ng S., Paull E.O., Carlin D., Goldstein T., Waltman P., RA Ellrott K., Zhu J., Haussler D., Gunaratne P.H., Xiao W., Shelton C., RA Gardner J., Penny R., Sherman M., Mallery D., Morris S., Paulauskis J., RA Burnett K., Shelton T., Signoretti S., Kaelin W.G., Choueiri T., RA Atkins M.B., Penny R., Burnett K., Mallery D., Curley E., Tickoo S., RA Reuter V., Kimryn Rathmell W., Thorne L., Boice L., Huang M., Fisher J.C., RA Marston Linehan W., Vocke C.D., Peterson J., Worrell R., Merino M.J., RA Schmidt L.S., Tamboli P., Czerniak B.A., Aldape K.D., Wood C.G., Boyd J., RA Weaver J., Iacocca M.V., Petrelli N., Witkin G., Brown J., Czerwinski C., RA Huelsenbeck-Dill L., Rabeno B., Myers J., Morrison C., Bergsten J., RA Eckman J., Harr J., Smith C., Tucker K., Anne Zach L., Bshara W., RA Gaudioso C., Morrison C., Dhir R., Maranchie J., Nelson J., Parwani A., RA Potapova O., Fedosenko K., Cheville J.C., Houston Thompson R., RA Signoretti S., Kaelin W.G., Atkins M.B., Tickoo S., Reuter V., RA Marston Linehan W., Vocke C.D., Peterson J., Merino M.J., Schmidt L.S., RA Tamboli P., Mosquera J.M., Rubin M.A., Blute M.L., Kimryn Rathmell W., RA Pihl T., Jensen M., Sfeir R., Kahn A., Chu A., Kothiyal P., Snyder E., RA Pontius J., Ayala B., Backus M., Walton J., Baboud J., Berton D., RA Nicholls M., Srinivasan D., Raman R., Girshik S., Kigonya P., Alonso S., RA Sanbhadti R., Barletta S., Pot D., Sheth M., Demchok J.A., Davidsen T., RA Wang Z., Yang L., Tarnuzzer R.W., Zhang J., Eley G., Ferguson M.L., RA Mills Shaw K.R., Guyer M.S., Ozenberger B.A., Sofia H.J.; RT "Comprehensive molecular characterization of clear cell renal cell RT carcinoma."; RL Nature 499:43-49(2013). RN [30] RP FUNCTION. RX PubMed=23325844; DOI=10.1093/nar/gks1472; RA Carvalho S., Raposo A.C., Martins F.B., Grosso A.R., Sridhara S.C., RA Rino J., Carmo-Fonseca M., de Almeida S.F.; RT "Histone methyltransferase SETD2 coordinates FACT recruitment with RT nucleosome dynamics during transcription."; RL Nucleic Acids Res. 41:2881-2893(2013). RN [31] RP FUNCTION. RX PubMed=24843002; DOI=10.7554/elife.02482; RA Carvalho S., Vitor A.C., Sridhara S.C., Martins F.B., Raposo A.C., RA Desterro J.M., Ferreira J., de Almeida S.F.; RT "SETD2 is required for DNA double-strand break repair and activation of the RT p53-mediated checkpoint."; RL Elife 3:E02482-E02482(2014). RN [32] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-321; SER-614 AND THR-1853, RP AND IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [33] RP INVOLVEMENT IN ALL, AND VARIANTS ALL ARG-2; GLY-19; ILE-267; PRO-470; RP ALA-499; 794-TYR--GLU-2564 DEL; PRO-1076; GLY-1093; ALA-1171; GLY-1351; RP GLU-1365; 1416-GLU--GLU-2564 DEL; ASN-1453; PRO-1609; MET-1663; PRO-1821; RP ALA-1915; VAL-1920; SER-2361 AND 2546-LYS--GLU-2564 DEL. RX PubMed=24662245; DOI=10.1038/ncomms4469; RA Mar B.G., Bullinger L.B., McLean K.M., Grauman P.V., Harris M.H., RA Stevenson K., Neuberg D.S., Sinha A.U., Sallan S.E., Silverman L.B., RA Kung A.L., Lo Nigro L., Ebert B.L., Armstrong S.A.; RT "Mutations in epigenetic regulators including SETD2 are gained during RT relapse in paediatric acute lymphoblastic leukaemia."; RL Nat. Commun. 5:3469-3469(2014). RN [34] RP INVOLVEMENT IN AML, INVOLVEMENT IN ALL, VARIANTS AML 70-ARG--GLU-2564 DEL; RP ASN-800; GLY-1397; SER-1804; TRP-2122; 2325-GLN--GLU-2564 DEL AND LEU-2505, RP AND VARIANTS ALL SER-226; ILE-761; ASN-1493; 1496-ARG--GLU-2564 DEL; RP GLN-1654; 2077-ARG--GLU-2564 DEL; ALA-2214 AND 2524-CYS--GLU-2564 DEL. RX PubMed=24509477; DOI=10.1038/ng.2894; RA Zhu X., He F., Zeng H., Ling S., Chen A., Wang Y., Yan X., Wei W., Pang Y., RA Cheng H., Hua C., Zhang Y., Yang X., Lu X., Cao L., Hao L., Dong L., RA Zou W., Wu J., Li X., Zheng S., Yan J., Zhou J., Zhang L., Mi S., Wang X., RA Zhang L., Zou Y., Chen Y., Geng Z., Wang J., Zhou J., Liu X., Wang J., RA Yuan W., Huang G., Cheng T., Wang Q.F.; RT "Identification of functional cooperative mutations of SETD2 in human acute RT leukemia."; RL Nat. Genet. 46:287-293(2014). RN [35] RP INVOLVEMENT IN LLS. RX PubMed=26084711; DOI=10.1007/s10803-015-2484-8; RA Lumish H.S., Wynn J., Devinsky O., Chung W.K.; RT "SETD2 mutation in a child with autism, intellectual disabilities and RT epilepsy."; RL J. Autism Dev. Disord. 45:3764-3770(2015). RN [36] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-637, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25755297; DOI=10.1074/mcp.o114.044792; RA Xiao Z., Chang J.G., Hendriks I.A., Sigurdsson J.O., Olsen J.V., RA Vertegaal A.C.; RT "System-wide analysis of SUMOylation dynamics in response to replication RT stress reveals novel small ubiquitin-like modified target proteins and RT acceptor lysines relevant for genome stability."; RL Mol. Cell. Proteomics 14:1419-1434(2015). RN [37] RP INVOLVEMENT IN RCC. RX PubMed=25728682; DOI=10.1038/onc.2015.24; RA Kanu N., Groenroos E., Martinez P., Burrell R.A., Yi Goh X., Bartkova J., RA Maya-Mendoza A., Mistrik M., Rowan A.J., Patel H., Rabinowitz A., East P., RA Wilson G., Santos C.R., McGranahan N., Gulati S., Gerlinger M., RA Birkbak N.J., Joshi T., Alexandrov L.B., Stratton M.R., Powles T., RA Matthews N., Bates P.A., Stewart A., Szallasi Z., Larkin J., Bartek J., RA Swanton C.; RT "SETD2 loss-of-function promotes renal cancer branched evolution through RT replication stress and impaired DNA repair."; RL Oncogene 34:5699-5708(2015). RN [38] RP FUNCTION AS ALPHA-TUBULIN METHYLTRANSFERASE, CATALYTIC ACTIVITY, AND RP INTERACTION WITH TUBA1A. RX PubMed=27518565; DOI=10.1016/j.cell.2016.07.005; RA Park I.Y., Powell R.T., Tripathi D.N., Dere R., Ho T.H., Blasius T.L., RA Chiang Y.C., Davis I.J., Fahey C.C., Hacker K.E., Verhey K.J., RA Bedford M.T., Jonasch E., Rathmell W.K., Walker C.L.; RT "Dual chromatin and cytoskeletal remodeling by SETD2."; RL Cell 166:950-962(2016). RN [39] RP POSSIBLE INVOLVEMENT IN LLS, AND FUNCTION. RX PubMed=27317772; DOI=10.1136/jmedgenet-2015-103638; RA Tlemsani C., Luscan A., Leulliot N., Bieth E., Afenjar A., Baujat G., RA Doco-Fenzy M., Goldenberg A., Lacombe D., Lambert L., Odent S., Pasche J., RA Sigaudy S., Buffet A., Violle-Poirsier C., Briand-Suleau A., Laurendeau I., RA Chin M., Saugier-Veber P., Vidaud D., Cormier-Daire V., Vidaud M., RA Pasmant E., Burglen L.; RT "SETD2 and DNMT3A screen in the Sotos-like syndrome French cohort."; RL J. Med. Genet. 53:743-751(2016). RN [40] RP FUNCTION, CATALYTIC ACTIVITY, INTERACTION WITH STAT1, AND MUTAGENESIS OF RP ARG-1625 AND CYS-1631. RX PubMed=28753426; DOI=10.1016/j.cell.2017.06.042; RA Chen K., Liu J., Liu S., Xia M., Zhang X., Han D., Jiang Y., Wang C., RA Cao X.; RT "Methyltransferase SETD2-mediated methylation of STAT1 is critical for RT interferon antiviral activity."; RL Cell 170:492-506(2017). RN [41] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-359; LYS-637 AND LYS-776, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=28112733; DOI=10.1038/nsmb.3366; RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C., RA Nielsen M.L.; RT "Site-specific mapping of the human SUMO proteome reveals co-modification RT with phosphorylation."; RL Nat. Struct. Mol. Biol. 24:325-336(2017). RN [42] RP INTERACTION WITH HNRNPL. RX PubMed=36537238; DOI=10.1093/nar/gkac1134; RA Kerschbamer E., Arnoldi M., Tripathi T., Pellegrini M., Maturi S., RA Erdin S., Salviato E., Di Leva F., Sebestyen E., Dassi E., Zarantonello G., RA Benelli M., Campos E., Basson M.A., Gusella J.F., Gustincich S., Piazza S., RA Demichelis F., Talkowski M.E., Ferrari F., Biagioli M.; RT "CHD8 suppression impacts on histone H3 lysine 36 trimethylation and alters RT RNA alternative splicing."; RL Nucleic Acids Res. 50:12809-12828(2022). RN [43] RP STRUCTURE BY NMR OF 2457-2564, INTERACTION WITH POLR2A, MUTAGENESIS OF RP ARG-2475; LYS-2476; GLN-2480; PHE-2481; VAL-2483; LYS-2506; ARG-2510; RP HIS-2514; GLY-2515; GLU-2528 AND GLU-2531, AND CHARACTERIZATION OF VARIANT RP AML LEU-2505. RX PubMed=16314571; DOI=10.1073/pnas.0506350102; RA Li M., Phatnani H.P., Guan Z., Sage H., Greenleaf A.L., Zhou P.; RT "Solution structure of the Set2-Rpb1 interacting domain of human Set2 and RT its interaction with the hyperphosphorylated C-terminal domain of Rpb1."; RL Proc. Natl. Acad. Sci. U.S.A. 102:17636-17641(2005). RN [44] {ECO:0007744|PDB:4FMU, ECO:0007744|PDB:4H12} RP X-RAY CRYSTALLOGRAPHY (1.99 ANGSTROMS) OF 1434-1711 IN COMPLEX WITH RP S-ADENOSYL-L-METHIONINE OR N-PROPYL SINEFUNGIN AND ZINC, FUNCTION, RP BIOPHYSICOCHEMICAL PROPERTIES, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND RP MUTAGENESIS OF PHE-1668; GLN-1669; ARG-1670 AND TYR-1671. RX PubMed=23043551; DOI=10.1021/ja307060p; RA Zheng W., Ibanez G., Wu H., Blum G., Zeng H., Dong A., Li F., Hajian T., RA Allali-Hassani A., Amaya M.F., Siarheyeva A., Yu W., Brown P.J., RA Schapira M., Vedadi M., Min J., Luo M.; RT "Sinefungin derivatives as inhibitors and structure probes of protein RT lysine methyltransferase SETD2."; RL J. Am. Chem. Soc. 134:18004-18014(2012). RN [45] RP X-RAY CRYSTALLOGRAPHY (1.50 ANGSTROMS) OF 1434-1711 IN COMPLEX WITH RP S-ADENOSYL-L-HOMOCYSTEINE AND ZINC, FUNCTION, CATALYTIC ACTIVITY, DOMAIN, RP AND MUTAGENESIS OF PHE-1589; TYR-1604; GLU-1636; THR-1637; PHE-1668 AND RP TYR-1671. RX PubMed=27474439; DOI=10.1101/gad.284323.116; RA Yang S., Zheng X., Lu C., Li G.M., Allis C.D., Li H.; RT "Molecular basis for oncohistone H3 recognition by SETD2 RT methyltransferase."; RL Genes Dev. 30:1611-1616(2016). RN [46] RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 1435-1711 IN COMPLEX WITH RP S-ADENOSYL-L-HOMOCYSTEINE AND ZINC, AND DOMAIN. RX PubMed=28256625; DOI=10.1038/srep43906; RA Zhang Y., Shan C.M., Wang J., Bao K., Tong L., Jia S.; RT "Molecular basis for the role of oncogenic histone mutations in modulating RT H3K36 methylation."; RL Sci. Rep. 7:43906-43906(2017). RN [47] RP VARIANT LLS TRP-1815. RX PubMed=24852293; DOI=10.1136/jmedgenet-2014-102402; RA Luscan A., Laurendeau I., Malan V., Francannet C., Odent S., Giuliano F., RA Lacombe D., Touraine R., Vidaud M., Pasmant E., Cormier-Daire V.; RT "Mutations in SETD2 cause a novel overgrowth condition."; RL J. Med. Genet. 51:512-517(2014). RN [48] RP VARIANT CYS-488. RX PubMed=26637798; DOI=10.1016/j.neuron.2015.11.009; RA D'Gama A.M., Pochareddy S., Li M., Jamuar S.S., Reiff R.E., Lam A.T., RA Sestan N., Walsh C.A.; RT "Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates RT Multiple Genetic Mechanisms."; RL Neuron 88:910-917(2015). RN [49] RP VARIANT RAPAS TRP-1740, VARIANT MRD70 GLN-1740, AND INVOLVEMENT IN RAPAS RP AND MRD70. RX PubMed=32710489; DOI=10.1002/ajmg.a.61724; RA Rabin R., Radmanesh A., Glass I.A., Dobyns W.B., Aldinger K.A., Shieh J.T., RA Romoser S., Bombei H., Dowsett L., Trapane P., Bernat J.A., Baker J., RA Mendelsohn N.J., Popp B., Siekmeyer M., Sorge I., Sansbury F.H., Watts P., RA Foulds N.C., Burton J., Hoganson G., Hurst J.A., Menzies L., Osio D., RA Kerecuk L., Cobben J.M., Jizi K., Jacquemont S., Belanger S.A., Loehner K., RA Veenstra-Knol H.E., Lemmink H.H., Keller-Ramey J., Wentzensen I.M., RA Punj S., McWalter K., Lenberg J., Ellsworth K.A., Radtke K., Akbarian S., RA Pappas J.; RT "Genotype-phenotype correlation at codon 1740 of SETD2."; RL Am. J. Med. Genet. A 182:2037-2048(2020). CC -!- FUNCTION: Histone methyltransferase that specifically trimethylates CC 'Lys-36' of histone H3 (H3K36me3) using dimethylated 'Lys-36' CC (H3K36me2) as substrate (PubMed:16118227, PubMed:19141475, CC PubMed:21526191, PubMed:21792193, PubMed:23043551, PubMed:27474439). It CC is capable of trimethylating unmethylated H3K36 (H3K36me0) in vitro CC (PubMed:19332550). Represents the main enzyme generating H3K36me3, a CC specific tag for epigenetic transcriptional activation (By similarity). CC Plays a role in chromatin structure modulation during elongation by CC coordinating recruitment of the FACT complex and by interacting with CC hyperphosphorylated POLR2A (PubMed:23325844). Acts as a key regulator CC of DNA mismatch repair in G1 and early S phase by generating H3K36me3, CC a mark required to recruit MSH6 subunit of the MutS alpha complex: CC early recruitment of the MutS alpha complex to chromatin to be CC replicated allows a quick identification of mismatch DNA to initiate CC the mismatch repair reaction (PubMed:23622243). Required for DNA CC double-strand break repair in response to DNA damage: acts by mediating CC formation of H3K36me3, promoting recruitment of RAD51 and DNA repair CC via homologous recombination (HR) (PubMed:24843002). Acts as a tumor CC suppressor (PubMed:24509477). H3K36me3 also plays an essential role in CC the maintenance of a heterochromatic state, by recruiting DNA CC methyltransferase DNMT3A (PubMed:27317772). H3K36me3 is also enhanced CC in intron-containing genes, suggesting that SETD2 recruitment is CC enhanced by splicing and that splicing is coupled to recruitment of CC elongating RNA polymerase (PubMed:21792193). Required during CC angiogenesis (By similarity). Required for endoderm development by CC promoting embryonic stem cell differentiation toward endoderm: acts by CC mediating formation of H3K36me3 in distal promoter regions of FGFR3, CC leading to regulate transcription initiation of FGFR3 (By similarity). CC In addition to histones, also mediates methylation of other proteins, CC such as tubulins and STAT1 (PubMed:27518565, PubMed:28753426). CC Trimethylates 'Lys-40' of alpha-tubulins such as TUBA1B (alpha- CC TubK40me3); alpha-TubK40me3 is required for normal mitosis and CC cytokinesis and may be a specific tag in cytoskeletal remodeling CC (PubMed:27518565). Involved in interferon-alpha-induced antiviral CC defense by mediating both monomethylation of STAT1 at 'Lys-525' and CC catalyzing H3K36me3 on promoters of some interferon-stimulated genes CC (ISGs) to activate gene transcription (PubMed:28753426). CC {ECO:0000250|UniProtKB:E9Q5F9, ECO:0000269|PubMed:16118227, CC ECO:0000269|PubMed:19141475, ECO:0000269|PubMed:21526191, CC ECO:0000269|PubMed:21792193, ECO:0000269|PubMed:23043551, CC ECO:0000269|PubMed:23325844, ECO:0000269|PubMed:23622243, CC ECO:0000269|PubMed:24509477, ECO:0000269|PubMed:24843002, CC ECO:0000269|PubMed:27317772, ECO:0000269|PubMed:27474439, CC ECO:0000269|PubMed:27518565, ECO:0000269|PubMed:28753426}. CC -!- FUNCTION: (Microbial infection) Recruited to the promoters of CC adenovirus 12 E1A gene in case of infection, possibly leading to CC regulate its expression. {ECO:0000269|PubMed:11461154}. CC -!- CATALYTIC ACTIVITY: CC Reaction=L-lysyl(36)-[histone H3] + 3 S-adenosyl-L-methionine = 3 H(+) CC + N(6),N(6),N(6)-trimethyl-L-lysyl(36)-[histone H3] + 3 S-adenosyl-L- CC homocysteine; Xref=Rhea:RHEA:60324, Rhea:RHEA-COMP:9785, Rhea:RHEA- CC COMP:15536, ChEBI:CHEBI:15378, ChEBI:CHEBI:29969, ChEBI:CHEBI:57856, CC ChEBI:CHEBI:59789, ChEBI:CHEBI:61961; EC=2.1.1.359; CC Evidence={ECO:0000269|PubMed:19332550, ECO:0000269|PubMed:23043551, CC ECO:0000269|PubMed:27474439}; CC -!- CATALYTIC ACTIVITY: CC Reaction=L-lysyl-[protein] + S-adenosyl-L-methionine = H(+) + N(6)- CC methyl-L-lysyl-[protein] + S-adenosyl-L-homocysteine; CC Xref=Rhea:RHEA:51736, Rhea:RHEA-COMP:9752, Rhea:RHEA-COMP:13053, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:29969, ChEBI:CHEBI:57856, CC ChEBI:CHEBI:59789, ChEBI:CHEBI:61929; CC Evidence={ECO:0000269|PubMed:23043551, ECO:0000269|PubMed:28753426}; CC -!- CATALYTIC ACTIVITY: CC Reaction=L-lysyl-[protein] + 3 S-adenosyl-L-methionine = 3 H(+) + CC N(6),N(6),N(6)-trimethyl-L-lysyl-[protein] + 3 S-adenosyl-L- CC homocysteine; Xref=Rhea:RHEA:54192, Rhea:RHEA-COMP:9752, Rhea:RHEA- CC COMP:13826, ChEBI:CHEBI:15378, ChEBI:CHEBI:29969, ChEBI:CHEBI:57856, CC ChEBI:CHEBI:59789, ChEBI:CHEBI:61961; CC Evidence={ECO:0000269|PubMed:27518565}; CC -!- ACTIVITY REGULATION: Specifically inhibited by sinefungin derivatives. CC N-propyl sinefungin (Pr-SNF) interacts preferentially with SETD2. CC {ECO:0000269|PubMed:23043551}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=1.21 uM for S-adenosyl-L-methionine {ECO:0000269|PubMed:23043551}; CC KM=0.42 uM for histone H3 {ECO:0000269|PubMed:23043551}; CC Note=kcat is 0.14 min(-1). {ECO:0000269|PubMed:23043551}; CC -!- SUBUNIT: Specifically interacts with hyperphosphorylated C-terminal CC domain (CTD) of RNA polymerase II large subunit (POLR2A): binds to CTD CC heptad repeats doubly phosphorylated on 'Ser-2' and 'Ser-5' of each CC heptad (PubMed:16118227, PubMed:16314571). Interacts with HTT CC (PubMed:11461154, PubMed:9700202, PubMed:10958656). Interacts with IWS1 CC (PubMed:19141475). Interacts with p53/TP53; leading to regulate CC p53/TP53 target genes (PubMed:18585004). Component of a complex with CC HNRNPL (PubMed:19332550, PubMed:36537238). Interacts with TUBA1A; the CC interaction is independent on alpha-tubulin acetylation on 'Lys-40' CC (PubMed:27518565). Interacts with STAT1 (PubMed:28753426). CC {ECO:0000269|PubMed:10958656, ECO:0000269|PubMed:11461154, CC ECO:0000269|PubMed:16118227, ECO:0000269|PubMed:16314571, CC ECO:0000269|PubMed:18585004, ECO:0000269|PubMed:19141475, CC ECO:0000269|PubMed:19332550, ECO:0000269|PubMed:27518565, CC ECO:0000269|PubMed:28753426, ECO:0000269|PubMed:9700202}. CC -!- INTERACTION: CC Q9BYW2; P42858: HTT; NbExp=4; IntAct=EBI-945869, EBI-466029; CC Q9BYW2; P84022: SMAD3; NbExp=2; IntAct=EBI-945869, EBI-347161; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:E9Q5F9}. CC Chromosome {ECO:0000250|UniProtKB:E9Q5F9}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q9BYW2-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9BYW2-2; Sequence=VSP_020915; CC Name=3; CC IsoId=Q9BYW2-3; Sequence=VSP_020914; CC -!- TISSUE SPECIFICITY: Ubiquitously expressed. CC {ECO:0000269|PubMed:11461154}. CC -!- DOMAIN: The low charge region mediates the transcriptional activation CC activity. {ECO:0000269|PubMed:16118227}. CC -!- DOMAIN: The catalytic SET domain binds histone H3 (PubMed:27474439, CC PubMed:28256625). It is also able to bind oncogenic histone H3 K36M/I CC found in a number of cancer types, in which histone H3 'Lys-36' is CC replaced by a Met or an Ile residue. When binding the oncogenic variant CC histone H3 K36M/I, the SET domain undergoes dramatic conformational CC change to accommodate the histone H3 peptide, leading to sequester and CC inhibit SETD2 activity and block global H3K36 methylation CC (PubMed:27474439, PubMed:28256625). {ECO:0000269|PubMed:27474439, CC ECO:0000269|PubMed:28256625}. CC -!- PTM: May be automethylated. {ECO:0000269|PubMed:16118227}. CC -!- DISEASE: Renal cell carcinoma (RCC) [MIM:144700]: Renal cell carcinoma CC is a heterogeneous group of sporadic or hereditary carcinoma derived CC from cells of the proximal renal tubular epithelium. It is CC subclassified into clear cell renal carcinoma (non-papillary CC carcinoma), papillary renal cell carcinoma, chromophobe renal cell CC carcinoma, collecting duct carcinoma with medullary carcinoma of the CC kidney, and unclassified renal cell carcinoma. Clear cell renal cell CC carcinoma is the most common subtype. {ECO:0000269|PubMed:20054297, CC ECO:0000269|PubMed:23622243, ECO:0000269|PubMed:23792563, CC ECO:0000269|PubMed:25728682}. Note=The disease may be caused by CC variants affecting the gene represented in this entry. Defects of SETD2 CC are associated with loss of DNA methylation at non-promoter regions CC (PubMed:23792563). SETD2 defects lead to aberrant and reduced CC nucleosome compaction and chromatin association of key replication CC proteins, such as MCM7 and DNA polymerase delta, leading to hinder CC replication fork progression and prevent loading of RAD51 homologous CC recombination repair factor at DNA breaks (PubMed:25728682). CC {ECO:0000269|PubMed:23792563, ECO:0000269|PubMed:25728682}. CC -!- DISEASE: Luscan-Lumish syndrome (LLS) [MIM:616831]: An autosomal CC dominant syndrome with a variable phenotype. Clinical features include CC macrocephaly, distinctive facial appearance, postnatal overgrowth, CC various degrees of learning difficulties, autism spectrum disorder, and CC intellectual disability. {ECO:0000269|PubMed:23160955, CC ECO:0000269|PubMed:24852293, ECO:0000269|PubMed:26084711, CC ECO:0000269|PubMed:27317772}. Note=The disease may be caused by CC variants affecting the gene represented in this entry. CC -!- DISEASE: Leukemia, acute lymphoblastic (ALL) [MIM:613065]: A subtype of CC acute leukemia, a cancer of the white blood cells. ALL is a malignant CC disease of bone marrow and the most common malignancy diagnosed in CC children. The malignant cells are lymphoid precursor cells CC (lymphoblasts) that are arrested in an early stage of development. The CC lymphoblasts replace the normal marrow elements, resulting in a marked CC decrease in the production of normal blood cells. Consequently, anemia, CC thrombocytopenia, and neutropenia occur to varying degrees. The CC lymphoblasts also proliferate in organs other than the marrow, CC particularly the liver, spleen, and lymphnodes. CC {ECO:0000269|PubMed:24509477, ECO:0000269|PubMed:24662245}. Note=The CC disease may be caused by variants affecting distinct genetic loci, CC including the gene represented in this entry. CC -!- DISEASE: Leukemia, acute myelogenous (AML) [MIM:601626]: A subtype of CC acute leukemia, a cancer of the white blood cells. AML is a malignant CC disease of bone marrow characterized by maturational arrest of CC hematopoietic precursors at an early stage of development. Clonal CC expansion of myeloid blasts occurs in bone marrow, blood, and other CC tissue. Myelogenous leukemias develop from changes in cells that CC normally produce neutrophils, basophils, eosinophils and monocytes. CC {ECO:0000269|PubMed:16314571, ECO:0000269|PubMed:24509477}. Note=The CC disease may be caused by variants affecting distinct genetic loci, CC including the gene represented in this entry. CC -!- DISEASE: Intellectual developmental disorder, autosomal dominant 70 CC (MRD70) [MIM:620157]: An autosomal dominant disorder characterized by CC mild global developmental delay, moderately impaired intellectual CC disability with speech difficulties, and behavioral abnormalities. CC {ECO:0000269|PubMed:32710489}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- DISEASE: Rabin-Pappas syndrome (RAPAS) [MIM:620155]: An autosomal CC dominant neurodevelopmental disorder characterized by severely impaired CC global development, intellectual disability, microcephaly, facial CC dysmorphism, and variable congenital anomalies affecting the skeletal, CC genitourinary, cardiac, and other organ systems. CC {ECO:0000269|PubMed:32710489}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the class V-like SAM-binding methyltransferase CC superfamily. Histone-lysine methyltransferase family. SET2 subfamily. CC {ECO:0000255|PROSITE-ProRule:PRU00190}. CC -!- SEQUENCE CAUTION: CC Sequence=AAF29041.1; Type=Frameshift; Evidence={ECO:0000305}; CC Sequence=AAH72440.1; Type=Erroneous termination; Note=Truncated C-terminus.; Evidence={ECO:0000305}; CC Sequence=AAI17163.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAI17165.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAT77612.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=AAT77613.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=BAB15367.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=BAB15367.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305}; CC Sequence=BAC87131.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC Sequence=CAC28349.1; Type=Erroneous termination; Note=Truncated C-terminus.; Evidence={ECO:0000305}; CC Sequence=CAD38601.2; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305}; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AC094020; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC127430; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AK026125; BAB15367.1; ALT_SEQ; mRNA. DR EMBL; AK127782; BAC87131.1; ALT_INIT; mRNA. DR EMBL; AK131371; BAD18522.1; -; mRNA. DR EMBL; AL713692; CAD28492.1; -; mRNA. DR EMBL; AL831959; CAD38601.2; ALT_INIT; mRNA. DR EMBL; AL833394; CAH10589.1; -; mRNA. DR EMBL; AJ238403; CAC28349.1; ALT_SEQ; mRNA. DR EMBL; BC072440; AAH72440.1; ALT_SEQ; mRNA. DR EMBL; BC090954; AAH90954.1; -; mRNA. DR EMBL; BC117162; AAI17163.1; ALT_INIT; mRNA. DR EMBL; BC117164; AAI17165.1; ALT_INIT; mRNA. DR EMBL; AY576987; AAT77612.1; ALT_INIT; mRNA. DR EMBL; AY576988; AAT77613.1; ALT_INIT; mRNA. DR EMBL; AB051519; BAB21823.2; -; mRNA. DR EMBL; AF161554; AAF29041.1; ALT_FRAME; mRNA. DR EMBL; AF049103; AAC26194.1; -; mRNA. DR EMBL; AF049610; AAC26846.1; -; mRNA. DR CCDS; CCDS2749.2; -. [Q9BYW2-1] DR RefSeq; NP_054878.5; NM_014159.6. [Q9BYW2-1] DR PDB; 2A7O; NMR; -; A=2457-2564. DR PDB; 2MDC; NMR; -; A=2385-2430. DR PDB; 2MDI; NMR; -; A=2377-2430. DR PDB; 2MDJ; NMR; -; A=2377-2430. DR PDB; 4FMU; X-ray; 2.10 A; A=1434-1711. DR PDB; 4H12; X-ray; 1.99 A; A=1434-1711. DR PDB; 5JJY; X-ray; 2.05 A; A=1434-1711. DR PDB; 5JLB; X-ray; 1.50 A; A=1434-1711. DR PDB; 5JLE; X-ray; 2.40 A; A=1434-1711. DR PDB; 5LSS; X-ray; 1.79 A; A=1433-1711. DR PDB; 5LSX; X-ray; 2.90 A; A=1433-1711. DR PDB; 5LSY; X-ray; 1.62 A; A=1433-1711. DR PDB; 5LSZ; X-ray; 1.62 A; A=1433-1711. DR PDB; 5LT6; X-ray; 2.05 A; A/B=1433-1711. DR PDB; 5LT7; X-ray; 1.51 A; A=1433-1711. DR PDB; 5LT8; X-ray; 1.57 A; A=1433-1711. DR PDB; 5V21; X-ray; 2.42 A; A=1435-1711. DR PDB; 5V22; X-ray; 2.40 A; A=1435-1711. DR PDB; 6J9J; X-ray; 1.78 A; A=1447-1703. DR PDB; 6VDB; X-ray; 2.30 A; A=1433-1711. DR PDB; 7EA8; EM; 3.10 A; L=1452-1696. DR PDB; 7EVR; X-ray; 1.80 A; B/D=2167-2192. DR PDB; 7EVS; X-ray; 1.60 A; C/D=2180-2192. DR PDB; 7LZB; X-ray; 2.28 A; A=1434-1711. DR PDB; 7LZD; X-ray; 1.80 A; A=1434-1711. DR PDB; 7LZF; X-ray; 2.47 A; A=1434-1711. DR PDB; 7TY2; X-ray; 2.44 A; A=1434-1711. DR PDB; 7TY3; X-ray; 2.30 A; A=1434-1711. DR PDBsum; 2A7O; -. DR PDBsum; 2MDC; -. DR PDBsum; 2MDI; -. DR PDBsum; 2MDJ; -. DR PDBsum; 4FMU; -. DR PDBsum; 4H12; -. DR PDBsum; 5JJY; -. DR PDBsum; 5JLB; -. DR PDBsum; 5JLE; -. DR PDBsum; 5LSS; -. DR PDBsum; 5LSX; -. DR PDBsum; 5LSY; -. DR PDBsum; 5LSZ; -. DR PDBsum; 5LT6; -. DR PDBsum; 5LT7; -. DR PDBsum; 5LT8; -. DR PDBsum; 5V21; -. DR PDBsum; 5V22; -. DR PDBsum; 6J9J; -. DR PDBsum; 6VDB; -. DR PDBsum; 7EA8; -. DR PDBsum; 7EVR; -. DR PDBsum; 7EVS; -. DR PDBsum; 7LZB; -. DR PDBsum; 7LZD; -. DR PDBsum; 7LZF; -. DR PDBsum; 7TY2; -. DR PDBsum; 7TY3; -. DR AlphaFoldDB; Q9BYW2; -. DR BMRB; Q9BYW2; -. DR EMDB; EMD-31040; -. DR SMR; Q9BYW2; -. DR BioGRID; 118845; 132. DR IntAct; Q9BYW2; 57. DR MINT; Q9BYW2; -. DR STRING; 9606.ENSP00000386759; -. DR BindingDB; Q9BYW2; -. DR ChEMBL; CHEMBL3108647; -. DR GlyGen; Q9BYW2; 2 sites, 1 O-linked glycan (2 sites). DR iPTMnet; Q9BYW2; -. DR PhosphoSitePlus; Q9BYW2; -. DR SwissPalm; Q9BYW2; -. DR BioMuta; SETD2; -. DR DMDM; 296452963; -. DR OGP; Q9BYW2; -. DR EPD; Q9BYW2; -. DR jPOST; Q9BYW2; -. DR MassIVE; Q9BYW2; -. DR MaxQB; Q9BYW2; -. DR PaxDb; 9606-ENSP00000386759; -. DR PeptideAtlas; Q9BYW2; -. DR ProteomicsDB; 79730; -. [Q9BYW2-1] DR ProteomicsDB; 79731; -. [Q9BYW2-2] DR ProteomicsDB; 79732; -. [Q9BYW2-3] DR Pumba; Q9BYW2; -. DR ABCD; Q9BYW2; 1 sequenced antibody. DR Antibodypedia; 29842; 401 antibodies from 34 providers. DR DNASU; 29072; -. DR Ensembl; ENST00000409792.4; ENSP00000386759.3; ENSG00000181555.22. [Q9BYW2-1] DR GeneID; 29072; -. DR KEGG; hsa:29072; -. DR MANE-Select; ENST00000409792.4; ENSP00000386759.3; NM_014159.7; NP_054878.5. DR UCSC; uc003cqs.4; human. [Q9BYW2-1] DR AGR; HGNC:18420; -. DR CTD; 29072; -. DR DisGeNET; 29072; -. DR GeneCards; SETD2; -. DR GeneReviews; SETD2; -. DR HGNC; HGNC:18420; SETD2. DR HPA; ENSG00000181555; Low tissue specificity. DR MalaCards; SETD2; -. DR MIM; 144700; phenotype. DR MIM; 601626; phenotype. DR MIM; 612778; gene. DR MIM; 613065; phenotype. DR MIM; 616831; phenotype. DR MIM; 620155; phenotype. DR MIM; 620157; phenotype. DR neXtProt; NX_Q9BYW2; -. DR OpenTargets; ENSG00000181555; -. DR Orphanet; 597738; Luscan-Lumish syndrome. DR Orphanet; 597743; SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome. DR Orphanet; 821; Sotos syndrome. DR PharmGKB; PA143485612; -. DR VEuPathDB; HostDB:ENSG00000181555; -. DR eggNOG; KOG4442; Eukaryota. DR GeneTree; ENSGT00940000160086; -. DR HOGENOM; CLU_000810_1_0_1; -. DR InParanoid; Q9BYW2; -. DR OMA; VAYDRIQ; -. DR OrthoDB; 950362at2759; -. DR PhylomeDB; Q9BYW2; -. DR TreeFam; TF106477; -. DR BioCyc; MetaCyc:HS17695-MONOMER; -. DR BRENDA; 2.1.1.359; 2681. DR PathwayCommons; Q9BYW2; -. DR Reactome; R-HSA-3214841; PKMTs methylate histone lysines. DR SignaLink; Q9BYW2; -. DR SIGNOR; Q9BYW2; -. DR BioGRID-ORCS; 29072; 309 hits in 1183 CRISPR screens. DR ChiTaRS; SETD2; human. DR EvolutionaryTrace; Q9BYW2; -. DR GeneWiki; SETD2; -. DR GenomeRNAi; 29072; -. DR Pharos; Q9BYW2; Tchem. DR PRO; PR:Q9BYW2; -. DR Proteomes; UP000005640; Chromosome 3. DR RNAct; Q9BYW2; Protein. DR Bgee; ENSG00000181555; Expressed in tendon of biceps brachii and 210 other cell types or tissues. DR ExpressionAtlas; Q9BYW2; baseline and differential. DR GO; GO:0005694; C:chromosome; ISS:UniProtKB. DR GO; GO:0005737; C:cytoplasm; IC:UniProt. DR GO; GO:0005654; C:nucleoplasm; TAS:Reactome. DR GO; GO:0005634; C:nucleus; ISS:UniProtKB. DR GO; GO:0043014; F:alpha-tubulin binding; IDA:UniProtKB. DR GO; GO:0140938; F:histone H3 methyltransferase activity; TAS:Reactome. DR GO; GO:0046975; F:histone H3K36 methyltransferase activity; IDA:UniProtKB. DR GO; GO:0140955; F:histone H3K36 trimethyltransferase activity; IEA:UniProtKB-EC. DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW. DR GO; GO:0016279; F:protein-lysine N-methyltransferase activity; IDA:UniProtKB. DR GO; GO:0001525; P:angiogenesis; IEA:Ensembl. DR GO; GO:0035441; P:cell migration involved in vasculogenesis; IEA:Ensembl. DR GO; GO:0060977; P:coronary vasculature morphogenesis; IEA:Ensembl. DR GO; GO:0051607; P:defense response to virus; IDA:UniProtKB. DR GO; GO:0048701; P:embryonic cranial skeleton morphogenesis; IEA:Ensembl. DR GO; GO:0060669; P:embryonic placenta morphogenesis; IEA:Ensembl. DR GO; GO:0035987; P:endodermal cell differentiation; ISS:UniProtKB. DR GO; GO:0030900; P:forebrain development; IEA:Ensembl. DR GO; GO:0048332; P:mesoderm morphogenesis; IEA:Ensembl. DR GO; GO:1902850; P:microtubule cytoskeleton organization involved in mitosis; IDA:UniProtKB. DR GO; GO:0006298; P:mismatch repair; IMP:UniProtKB. DR GO; GO:0001763; P:morphogenesis of a branching structure; IEA:Ensembl. DR GO; GO:0001843; P:neural tube closure; IEA:Ensembl. DR GO; GO:0034728; P:nucleosome organization; IMP:UniProtKB. DR GO; GO:0018023; P:peptidyl-lysine trimethylation; IDA:UniProtKB. DR GO; GO:0060039; P:pericardium development; IEA:Ensembl. DR GO; GO:0010508; P:positive regulation of autophagy; IDA:UniProt. DR GO; GO:0032727; P:positive regulation of interferon-alpha production; IDA:UniProtKB. DR GO; GO:0045778; P:positive regulation of ossification; IEA:Ensembl. DR GO; GO:0032465; P:regulation of cytokinesis; IDA:UniProtKB. DR GO; GO:0006355; P:regulation of DNA-templated transcription; IEA:InterPro. DR GO; GO:0010569; P:regulation of double-strand break repair via homologous recombination; IDA:UniProtKB. DR GO; GO:0010468; P:regulation of gene expression; IBA:GO_Central. DR GO; GO:0010793; P:regulation of mRNA export from nucleus; IMP:UniProtKB. DR GO; GO:1905634; P:regulation of protein localization to chromatin; IDA:UniProtKB. DR GO; GO:0043279; P:response to alkaloid; IEA:Ensembl. DR GO; GO:0010038; P:response to metal ion; IEA:Ensembl. DR GO; GO:0014070; P:response to organic cyclic compound; IEA:Ensembl. DR GO; GO:0034340; P:response to type I interferon; IDA:UniProtKB. DR GO; GO:0048864; P:stem cell development; IEA:Ensembl. DR GO; GO:0048863; P:stem cell differentiation; ISS:UniProtKB. DR GO; GO:0006368; P:transcription elongation by RNA polymerase II; IMP:UniProtKB. DR CDD; cd19172; SET_SETD2; 1. DR CDD; cd00201; WW; 1. DR Gene3D; 2.20.70.10; -; 1. DR Gene3D; 1.20.930.10; Conserved domain common to transcription factors TFIIS, elongin A, CRSP70; 1. DR Gene3D; 2.170.270.10; SET domain; 1. DR Gene3D; 1.10.1740.100; Set2, Rpb1 interacting domain; 1. DR InterPro; IPR006560; AWS_dom. DR InterPro; IPR003616; Post-SET_dom. DR InterPro; IPR001214; SET_dom. DR InterPro; IPR046341; SET_dom_sf. DR InterPro; IPR044437; SETD2/Set2_SET. DR InterPro; IPR042294; SETD2_animal. DR InterPro; IPR013257; SRI. DR InterPro; IPR038190; SRI_sf. DR InterPro; IPR035441; TFIIS/LEDGF_dom_sf. DR InterPro; IPR001202; WW_dom. DR InterPro; IPR036020; WW_dom_sf. DR PANTHER; PTHR46711; HISTONE-LYSINE N-METHYLTRANSFERASE SETD2; 1. DR PANTHER; PTHR46711:SF1; HISTONE-LYSINE N-METHYLTRANSFERASE SETD2; 1. DR Pfam; PF17907; AWS; 1. DR Pfam; PF00856; SET; 1. DR Pfam; PF08236; SRI; 1. DR Pfam; PF00397; WW; 1. DR SMART; SM00570; AWS; 1. DR SMART; SM00508; PostSET; 1. DR SMART; SM00317; SET; 1. DR SMART; SM00456; WW; 1. DR SUPFAM; SSF82199; SET domain; 1. DR SUPFAM; SSF51045; WW domain; 1. DR PROSITE; PS51215; AWS; 1. DR PROSITE; PS50868; POST_SET; 1. DR PROSITE; PS50280; SET; 1. DR PROSITE; PS01159; WW_DOMAIN_1; 1. DR PROSITE; PS50020; WW_DOMAIN_2; 1. DR Genevisible; Q9BYW2; HS. PE 1: Evidence at protein level; KW 3D-structure; Activator; Alternative splicing; Antiviral defense; KW Autism spectrum disorder; Chromatin regulator; Chromosome; Coiled coil; KW Developmental protein; Differentiation; Disease variant; DNA damage; KW DNA repair; Host-virus interaction; Immunity; Innate immunity; KW Intellectual disability; Isopeptide bond; Metal-binding; Methyltransferase; KW Nucleus; Phosphoprotein; Reference proteome; S-adenosyl-L-methionine; KW Transcription; Transcription regulation; Transferase; Tumor suppressor; KW Ubl conjugation; Zinc. FT CHAIN 1..2564 FT /note="Histone-lysine N-methyltransferase SETD2" FT /id="PRO_0000252367" FT DOMAIN 1494..1548 FT /note="AWS" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00562" FT DOMAIN 1550..1667 FT /note="SET" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00190" FT DOMAIN 1674..1690 FT /note="Post-SET" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00155" FT DOMAIN 2389..2422 FT /note="WW" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00224" FT REGION 1..30 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 180..211 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 272..561 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 607..626 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 964..995 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1036..1101 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1133..1233 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1264..1352 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1393..1443 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1418..1714 FT /note="Interaction with TUBA1A" FT /evidence="ECO:0000269|PubMed:27518565" FT REGION 1831..1872 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 1921..2142 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 2137..2366 FT /note="Low charge region" FT /evidence="ECO:0000269|PubMed:16118227" FT REGION 2439..2465 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 2457..2564 FT /note="Interaction with POLR2A" FT /evidence="ECO:0000269|PubMed:16314571" FT COILED 2117..2146 FT /evidence="ECO:0000255" FT COMPBIAS 185..201 FT /note="Pro residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 276..297 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 298..327 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 340..411 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 424..471 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 486..526 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 544..560 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 967..993 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1061..1094 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1140..1154 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1164..1179 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1211..1233 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1393..1432 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1831..1867 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1924..1949 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 1952..1971 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 2011..2046 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 2055..2080 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 2090..2130 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 2449..2465 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT BINDING 1499 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:23043551, FT ECO:0000269|PubMed:27474439, ECO:0000269|PubMed:28256625, FT ECO:0007744|PDB:4FMU, ECO:0007744|PDB:4H12, FT ECO:0007744|PDB:5JJY, ECO:0007744|PDB:5JLB, FT ECO:0007744|PDB:5JLE, ECO:0007744|PDB:5V21, FT ECO:0007744|PDB:5V22" FT BINDING 1501 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:23043551, FT ECO:0000269|PubMed:27474439, ECO:0000269|PubMed:28256625, FT ECO:0007744|PDB:4FMU, ECO:0007744|PDB:4H12, FT ECO:0007744|PDB:5JJY, ECO:0007744|PDB:5JLB, FT ECO:0007744|PDB:5JLE, ECO:0007744|PDB:5V21, FT ECO:0007744|PDB:5V22" FT BINDING 1516 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:23043551, FT ECO:0000269|PubMed:27474439, ECO:0000269|PubMed:28256625, FT ECO:0007744|PDB:4FMU, ECO:0007744|PDB:4H12, FT ECO:0007744|PDB:5JJY, ECO:0007744|PDB:5JLB, FT ECO:0007744|PDB:5JLE, ECO:0007744|PDB:5V21, FT ECO:0007744|PDB:5V22" FT BINDING 1516 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:23043551, FT ECO:0000269|PubMed:27474439, ECO:0000269|PubMed:28256625, FT ECO:0007744|PDB:4FMU, ECO:0007744|PDB:4H12, FT ECO:0007744|PDB:5JJY, ECO:0007744|PDB:5JLB, FT ECO:0007744|PDB:5JLE, ECO:0007744|PDB:5V21, FT ECO:0007744|PDB:5V22" FT BINDING 1520 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:23043551, FT ECO:0000269|PubMed:27474439, ECO:0000269|PubMed:28256625, FT ECO:0007744|PDB:4FMU, ECO:0007744|PDB:4H12, FT ECO:0007744|PDB:5JJY, ECO:0007744|PDB:5JLB, FT ECO:0007744|PDB:5JLE, ECO:0007744|PDB:5V21, FT ECO:0007744|PDB:5V22" FT BINDING 1529 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:23043551, FT ECO:0000269|PubMed:27474439, ECO:0000269|PubMed:28256625, FT ECO:0007744|PDB:4FMU, ECO:0007744|PDB:4H12, FT ECO:0007744|PDB:5JJY, ECO:0007744|PDB:5JLB, FT ECO:0007744|PDB:5JLE, ECO:0007744|PDB:5V21, FT ECO:0007744|PDB:5V22" FT BINDING 1533 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:23043551, FT ECO:0000269|PubMed:27474439, ECO:0000269|PubMed:28256625, FT ECO:0007744|PDB:4FMU, ECO:0007744|PDB:4H12, FT ECO:0007744|PDB:5JJY, ECO:0007744|PDB:5JLB, FT ECO:0007744|PDB:5JLE, ECO:0007744|PDB:5V21, FT ECO:0007744|PDB:5V22" FT BINDING 1539 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:23043551, FT ECO:0000269|PubMed:27474439, ECO:0000269|PubMed:28256625, FT ECO:0007744|PDB:4FMU, ECO:0007744|PDB:4H12, FT ECO:0007744|PDB:5JJY, ECO:0007744|PDB:5JLB, FT ECO:0007744|PDB:5JLE, ECO:0007744|PDB:5V21, FT ECO:0007744|PDB:5V22" FT BINDING 1560..1562 FT /ligand="S-adenosyl-L-methionine" FT /ligand_id="ChEBI:CHEBI:59789" FT /evidence="ECO:0000269|PubMed:23043551, FT ECO:0000269|PubMed:27474439, ECO:0000269|PubMed:28256625, FT ECO:0007744|PDB:4H12, ECO:0007744|PDB:5JJY, FT ECO:0007744|PDB:5JLB, ECO:0007744|PDB:5JLE, FT ECO:0007744|PDB:5V22" FT BINDING 1603..1605 FT /ligand="S-adenosyl-L-methionine" FT /ligand_id="ChEBI:CHEBI:59789" FT /evidence="ECO:0000269|PubMed:23043551, FT ECO:0000269|PubMed:27474439, ECO:0000269|PubMed:28256625, FT ECO:0007744|PDB:4H12, ECO:0007744|PDB:5JJY, FT ECO:0007744|PDB:5JLB, ECO:0007744|PDB:5JLE, FT ECO:0007744|PDB:5V22" FT BINDING 1628..1629 FT /ligand="S-adenosyl-L-methionine" FT /ligand_id="ChEBI:CHEBI:59789" FT /evidence="ECO:0000269|PubMed:23043551, FT ECO:0000269|PubMed:27474439, ECO:0000269|PubMed:28256625, FT ECO:0007744|PDB:4H12, ECO:0007744|PDB:5JJY, FT ECO:0007744|PDB:5JLB, ECO:0007744|PDB:5JLE, FT ECO:0007744|PDB:5V22" FT BINDING 1631 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000269|PubMed:23043551, FT ECO:0000269|PubMed:27474439, ECO:0000269|PubMed:28256625, FT ECO:0007744|PDB:4FMU, ECO:0007744|PDB:4H12, FT ECO:0007744|PDB:5JJY, ECO:0007744|PDB:5JLB, FT ECO:0007744|PDB:5JLE, ECO:0007744|PDB:5V21, FT ECO:0007744|PDB:5V22" FT BINDING 1676 FT /ligand="S-adenosyl-L-methionine" FT /ligand_id="ChEBI:CHEBI:59789" FT /evidence="ECO:0000269|PubMed:23043551, FT ECO:0000269|PubMed:27474439, ECO:0000269|PubMed:28256625, FT ECO:0007744|PDB:4H12, ECO:0007744|PDB:5JJY, FT ECO:0007744|PDB:5JLB, ECO:0007744|PDB:5JLE, FT ECO:0007744|PDB:5V22" FT BINDING 1678 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000269|PubMed:23043551, FT ECO:0000269|PubMed:27474439, ECO:0000269|PubMed:28256625, FT ECO:0007744|PDB:4FMU, ECO:0007744|PDB:4H12, FT ECO:0007744|PDB:5JJY, ECO:0007744|PDB:5JLB, FT ECO:0007744|PDB:5JLE, ECO:0007744|PDB:5V21, FT ECO:0007744|PDB:5V22" FT BINDING 1679 FT /ligand="S-adenosyl-L-methionine" FT /ligand_id="ChEBI:CHEBI:59789" FT /evidence="ECO:0000269|PubMed:23043551, FT ECO:0000269|PubMed:27474439, ECO:0000269|PubMed:28256625, FT ECO:0007744|PDB:4H12, ECO:0007744|PDB:5JJY, FT ECO:0007744|PDB:5JLB, ECO:0007744|PDB:5JLE, FT ECO:0007744|PDB:5V22" FT BINDING 1680 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000269|PubMed:23043551, FT ECO:0000269|PubMed:27474439, ECO:0000269|PubMed:28256625, FT ECO:0007744|PDB:4FMU, ECO:0007744|PDB:4H12, FT ECO:0007744|PDB:5JJY, ECO:0007744|PDB:5JLB, FT ECO:0007744|PDB:5JLE, ECO:0007744|PDB:5V21, FT ECO:0007744|PDB:5V22" FT BINDING 1685 FT /ligand="Zn(2+)" FT /ligand_id="ChEBI:CHEBI:29105" FT /ligand_label="3" FT /evidence="ECO:0000269|PubMed:23043551, FT ECO:0000269|PubMed:27474439, ECO:0000269|PubMed:28256625, FT ECO:0007744|PDB:4FMU, ECO:0007744|PDB:4H12, FT ECO:0007744|PDB:5JJY, ECO:0007744|PDB:5JLB, FT ECO:0007744|PDB:5JLE, ECO:0007744|PDB:5V21, FT ECO:0007744|PDB:5V22" FT MOD_RES 131 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332, FT ECO:0007744|PubMed:23186163" FT MOD_RES 321 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:24275569" FT MOD_RES 323 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:20068231, FT ECO:0007744|PubMed:21406692" FT MOD_RES 344 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 422 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 532 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 614 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163, FT ECO:0007744|PubMed:24275569" FT MOD_RES 624 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT MOD_RES 626 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 698 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:E9Q5F9" FT MOD_RES 708 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332" FT MOD_RES 744 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:19690332, FT ECO:0007744|PubMed:23186163" FT MOD_RES 754 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:19690332, ECO:0007744|PubMed:21406692, FT ECO:0007744|PubMed:23186163" FT MOD_RES 1098 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 1228 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18220336, FT ECO:0007744|PubMed:18669648, ECO:0007744|PubMed:23186163" FT MOD_RES 1413 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:E9Q5F9" FT MOD_RES 1415 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:E9Q5F9" FT MOD_RES 1417 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:E9Q5F9" FT MOD_RES 1696 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 1844 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:E9Q5F9" FT MOD_RES 1845 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:E9Q5F9" FT MOD_RES 1853 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:23186163, FT ECO:0007744|PubMed:24275569" FT MOD_RES 1872 FT /note="Phosphothreonine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:23186163" FT MOD_RES 1888 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 1952 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 1980 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:E9Q5F9" FT MOD_RES 1988 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:E9Q5F9" FT MOD_RES 1995 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:E9Q5F9" FT MOD_RES 2080 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:23186163" FT MOD_RES 2082 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163" FT CROSSLNK 359 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" FT CROSSLNK 637 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:25755297, FT ECO:0007744|PubMed:28112733" FT CROSSLNK 776 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" FT VAR_SEQ 1573..2564 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000303|PubMed:17974005" FT /id="VSP_020914" FT VAR_SEQ 1715..2564 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|Ref.7" FT /id="VSP_020915" FT VARIANT 2 FT /note="K -> R (in ALL; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:24662245" FT /id="VAR_079054" FT VARIANT 19 FT /note="E -> G (in ALL; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:24662245" FT /id="VAR_079055" FT VARIANT 70..2564 FT /note="Missing (in AML; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:24509477" FT /id="VAR_079056" FT VARIANT 226 FT /note="P -> S (in ALL; uncertain significance; somatic FT mutation; dbSNP:rs780963440)" FT /evidence="ECO:0000269|PubMed:24509477" FT /id="VAR_079057" FT VARIANT 267 FT /note="V -> I (in ALL; uncertain significance; somatic FT mutation; dbSNP:rs186148199)" FT /evidence="ECO:0000269|PubMed:24662245" FT /id="VAR_079058" FT VARIANT 470 FT /note="S -> P (in ALL; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:24662245" FT /id="VAR_079059" FT VARIANT 488 FT /note="Y -> C (found in a patient with autism; uncertain FT significance; dbSNP:rs757781388)" FT /evidence="ECO:0000269|PubMed:26637798" FT /id="VAR_078707" FT VARIANT 499 FT /note="T -> A (in ALL; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:24662245" FT /id="VAR_079060" FT VARIANT 761 FT /note="M -> I (in ALL; uncertain significance; somatic FT mutation; dbSNP:rs188887061)" FT /evidence="ECO:0000269|PubMed:24509477" FT /id="VAR_079061" FT VARIANT 768 FT /note="V -> L (in dbSNP:rs9311404)" FT /id="VAR_027839" FT VARIANT 794..2564 FT /note="Missing (in ALL; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:24662245" FT /id="VAR_079062" FT VARIANT 800 FT /note="S -> N (in AML; uncertain significance; somatic FT mutation; dbSNP:rs1169288572)" FT /evidence="ECO:0000269|PubMed:24509477" FT /id="VAR_079063" FT VARIANT 902 FT /note="E -> Q (in dbSNP:rs58906143)" FT /id="VAR_061216" FT VARIANT 1076 FT /note="S -> P (in ALL; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:24662245" FT /id="VAR_079064" FT VARIANT 1093 FT /note="S -> G (in ALL; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:24662245" FT /id="VAR_079065" FT VARIANT 1171 FT /note="T -> A (in ALL; uncertain significance; somatic FT mutation; dbSNP:rs540476365)" FT /evidence="ECO:0000269|PubMed:24662245" FT /id="VAR_079066" FT VARIANT 1351 FT /note="D -> G (in ALL; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:24662245" FT /id="VAR_079067" FT VARIANT 1365 FT /note="G -> E (in ALL; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:24662245" FT /id="VAR_079068" FT VARIANT 1397 FT /note="D -> G (in AML; uncertain significance; somatic FT mutation; dbSNP:rs754921650)" FT /evidence="ECO:0000269|PubMed:24509477" FT /id="VAR_079069" FT VARIANT 1416..2564 FT /note="Missing (in ALL; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:24662245" FT /id="VAR_079070" FT VARIANT 1453 FT /note="D -> N (in ALL; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:24662245" FT /id="VAR_079071" FT VARIANT 1493 FT /note="D -> N (in ALL; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:24509477" FT /id="VAR_079072" FT VARIANT 1496..2564 FT /note="Missing (in ALL; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:24509477" FT /id="VAR_079073" FT VARIANT 1609 FT /note="L -> P (in ALL; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:24662245" FT /id="VAR_079074" FT VARIANT 1654 FT /note="K -> Q (in ALL; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:24509477" FT /id="VAR_079075" FT VARIANT 1663 FT /note="T -> M (in ALL; uncertain significance; somatic FT mutation; dbSNP:rs1478147351)" FT /evidence="ECO:0000269|PubMed:24662245" FT /id="VAR_079076" FT VARIANT 1733 FT /note="N -> D (in RCC; defects in recruitment of the MutS FT alpha complex)" FT /evidence="ECO:0000269|PubMed:23622243" FT /id="VAR_069812" FT VARIANT 1740 FT /note="R -> Q (in MRD70)" FT /evidence="ECO:0000269|PubMed:32710489" FT /id="VAR_087881" FT VARIANT 1740 FT /note="R -> W (in RAPAS)" FT /evidence="ECO:0000269|PubMed:32710489" FT /id="VAR_087882" FT VARIANT 1769 FT /note="S -> P (in RCC; defects in recruitment of the MutS FT alpha complex)" FT /evidence="ECO:0000269|PubMed:23622243" FT /id="VAR_069813" FT VARIANT 1804 FT /note="L -> S (in AML; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:24509477" FT /id="VAR_079077" FT VARIANT 1815 FT /note="L -> W (in LLS; uncertain significance; FT dbSNP:rs869025570)" FT /evidence="ECO:0000269|PubMed:24852293" FT /id="VAR_076536" FT VARIANT 1821 FT /note="L -> P (in ALL; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:24662245" FT /id="VAR_079078" FT VARIANT 1868 FT /note="A -> D (in dbSNP:rs11721074)" FT /id="VAR_027840" FT VARIANT 1915 FT /note="V -> A (in ALL; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:24662245" FT /id="VAR_079079" FT VARIANT 1920 FT /note="E -> V (in ALL; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:24662245" FT /id="VAR_079080" FT VARIANT 1962 FT /note="P -> L (in dbSNP:rs4082155)" FT /evidence="ECO:0000269|PubMed:11214970, FT ECO:0000269|PubMed:15489334" FT /id="VAR_027841" FT VARIANT 2077..2564 FT /note="Missing (in ALL; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:24509477" FT /id="VAR_079081" FT VARIANT 2122 FT /note="R -> W (in AML; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:24509477" FT /id="VAR_079082" FT VARIANT 2214 FT /note="T -> A (in ALL; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:24509477" FT /id="VAR_079083" FT VARIANT 2325..2564 FT /note="Missing (in AML; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:24509477" FT /id="VAR_079084" FT VARIANT 2361 FT /note="P -> S (in ALL; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:24662245" FT /id="VAR_079085" FT VARIANT 2505 FT /note="F -> L (in AML; uncertain significance; somatic FT mutation; impairs interaction with hyperphosphorylated FT POLR2A)" FT /evidence="ECO:0000269|PubMed:16314571, FT ECO:0000269|PubMed:24509477" FT /id="VAR_079086" FT VARIANT 2524..2564 FT /note="Missing (in ALL; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:24509477" FT /id="VAR_079087" FT VARIANT 2546..2564 FT /note="Missing (in ALL; uncertain significance; somatic FT mutation)" FT /evidence="ECO:0000269|PubMed:24662245" FT /id="VAR_079088" FT MUTAGEN 1589 FT /note="F->A: Strongly reduced methyltransferase activity." FT /evidence="ECO:0000269|PubMed:27474439" FT MUTAGEN 1604 FT /note="Y->A: Increased methyltransferase activity." FT /evidence="ECO:0000269|PubMed:27474439" FT MUTAGEN 1625 FT /note="R->H,G: Loss of methyltransferase activity. FT Abolishes ability to monomethylate STAT1." FT /evidence="ECO:0000269|PubMed:16118227, FT ECO:0000269|PubMed:28753426" FT MUTAGEN 1631 FT /note="C->A: Does not affect methyltransferase activity." FT /evidence="ECO:0000269|PubMed:28753426" FT MUTAGEN 1636 FT /note="E->A: Increased methyltransferase activity." FT /evidence="ECO:0000269|PubMed:27474439" FT MUTAGEN 1637 FT /note="T->A: Increased methyltransferase activity." FT /evidence="ECO:0000269|PubMed:27474439" FT MUTAGEN 1668 FT /note="F->A: Strongly reduced methyltransferase activity." FT /evidence="ECO:0000269|PubMed:23043551, FT ECO:0000269|PubMed:27474439" FT MUTAGEN 1669 FT /note="Q->A: Loss of methyltransferase activity." FT /evidence="ECO:0000269|PubMed:23043551" FT MUTAGEN 1670 FT /note="R->A,V,L,I,F: Impaired methyltransferase activity." FT /evidence="ECO:0000269|PubMed:23043551" FT MUTAGEN 1670 FT /note="R->P,W,K,Q: Loss of methyltransferase activity." FT /evidence="ECO:0000269|PubMed:23043551" FT MUTAGEN 1671 FT /note="Y->A: Strongly reduced methyltransferase activity." FT /evidence="ECO:0000269|PubMed:23043551, FT ECO:0000269|PubMed:27474439" FT MUTAGEN 2475 FT /note="R->A: Does not affect interaction with FT hyperphosphorylated POLR2A." FT /evidence="ECO:0000269|PubMed:16314571" FT MUTAGEN 2476 FT /note="K->A: Does not affect interaction with FT hyperphosphorylated POLR2A." FT /evidence="ECO:0000269|PubMed:16314571" FT MUTAGEN 2480 FT /note="Q->A: Does not affect interaction with FT hyperphosphorylated POLR2A." FT /evidence="ECO:0000269|PubMed:16314571" FT MUTAGEN 2481 FT /note="F->A: Does not affect interaction with FT hyperphosphorylated POLR2A." FT /evidence="ECO:0000269|PubMed:16314571" FT MUTAGEN 2483 FT /note="V->A: Impairs interaction with hyperphosphorylated FT POLR2A." FT /evidence="ECO:0000269|PubMed:16314571" FT MUTAGEN 2506 FT /note="K->A: Impairs interaction with hyperphosphorylated FT POLR2A." FT /evidence="ECO:0000269|PubMed:16314571" FT MUTAGEN 2510 FT /note="R->A: Impairs interaction with hyperphosphorylated FT POLR2A." FT /evidence="ECO:0000269|PubMed:16314571" FT MUTAGEN 2514 FT /note="H->A: Impairs interaction with hyperphosphorylated FT POLR2A." FT /evidence="ECO:0000269|PubMed:16314571" FT MUTAGEN 2515 FT /note="G->A,T: Does not affect interaction with FT hyperphosphorylated POLR2A." FT /evidence="ECO:0000269|PubMed:16314571" FT MUTAGEN 2528 FT /note="E->A: Increases interaction with hyperphosphorylated FT POLR2A; when associated with A-2531." FT /evidence="ECO:0000269|PubMed:16314571" FT MUTAGEN 2531 FT /note="E->A: Increases interaction with hyperphosphorylated FT POLR2A; when associated with A-2528." FT /evidence="ECO:0000269|PubMed:16314571" FT CONFLICT 448 FT /note="R -> Q (in Ref. 2; BAD18522)" FT /evidence="ECO:0000305" FT CONFLICT 455 FT /note="A -> V (in Ref. 3; CAD38601)" FT /evidence="ECO:0000305" FT CONFLICT 912 FT /note="L -> P (in Ref. 2; BAB15367)" FT /evidence="ECO:0000305" FT CONFLICT 964 FT /note="E -> K (in Ref. 4; CAC28349, 6; AAT77612 and 7; FT AAT77613)" FT /evidence="ECO:0000305" FT CONFLICT 1080 FT /note="M -> I (in Ref. 2; BAC87131)" FT /evidence="ECO:0000305" FT CONFLICT 1080 FT /note="M -> T (in Ref. 3; CAD38601)" FT /evidence="ECO:0000305" FT CONFLICT 1212 FT /note="V -> F (in Ref. 2; BAD18522)" FT /evidence="ECO:0000305" FT CONFLICT 1269 FT /note="T -> A (in Ref. 4; CAC28349, 6; AAT77612 and 7; FT AAT77613)" FT /evidence="ECO:0000305" FT CONFLICT 1338 FT /note="E -> G (in Ref. 2; BAB15367)" FT /evidence="ECO:0000305" FT CONFLICT 1498 FT /note="Q -> R (in Ref. 3; CAD38601)" FT /evidence="ECO:0000305" FT CONFLICT 1706 FT /note="K -> N (in Ref. 10; AAF29041)" FT /evidence="ECO:0000305" FT CONFLICT 1736 FT /note="L -> P (in Ref. 4; CAC28349 and 6; AAT77612)" FT /evidence="ECO:0000305" FT STRAND 1448..1450 FT /evidence="ECO:0007829|PDB:5JLB" FT HELIX 1451..1455 FT /evidence="ECO:0007829|PDB:5JLB" FT HELIX 1457..1465 FT /evidence="ECO:0007829|PDB:5JLB" FT STRAND 1472..1474 FT /evidence="ECO:0007829|PDB:7EA8" FT STRAND 1480..1483 FT /evidence="ECO:0007829|PDB:5JLB" FT TURN 1490..1493 FT /evidence="ECO:0007829|PDB:7EA8" FT HELIX 1506..1511 FT /evidence="ECO:0007829|PDB:5JLB" FT HELIX 1521..1524 FT /evidence="ECO:0007829|PDB:5JLB" FT STRAND 1531..1533 FT /evidence="ECO:0007829|PDB:5LSX" FT HELIX 1536..1538 FT /evidence="ECO:0007829|PDB:5JLB" FT STRAND 1539..1541 FT /evidence="ECO:0007829|PDB:5JLE" FT TURN 1543..1547 FT /evidence="ECO:0007829|PDB:5JLB" FT STRAND 1552..1556 FT /evidence="ECO:0007829|PDB:5JLB" FT STRAND 1558..1560 FT /evidence="ECO:0007829|PDB:5JLB" FT STRAND 1562..1568 FT /evidence="ECO:0007829|PDB:5JLB" FT STRAND 1575..1578 FT /evidence="ECO:0007829|PDB:5JLB" FT STRAND 1582..1584 FT /evidence="ECO:0007829|PDB:5JLB" FT HELIX 1586..1598 FT /evidence="ECO:0007829|PDB:5JLB" FT STRAND 1606..1610 FT /evidence="ECO:0007829|PDB:5JLB" FT STRAND 1613..1616 FT /evidence="ECO:0007829|PDB:5JLB" FT STRAND 1618..1621 FT /evidence="ECO:0007829|PDB:5JLB" FT HELIX 1623..1626 FT /evidence="ECO:0007829|PDB:5JLB" FT STRAND 1634..1642 FT /evidence="ECO:0007829|PDB:5JLB" FT STRAND 1645..1654 FT /evidence="ECO:0007829|PDB:5JLB" FT STRAND 1661..1664 FT /evidence="ECO:0007829|PDB:5JLB" FT HELIX 1667..1670 FT /evidence="ECO:0007829|PDB:5LT7" FT STRAND 1672..1674 FT /evidence="ECO:0007829|PDB:5JLB" FT STRAND 1675..1677 FT /evidence="ECO:0007829|PDB:5LT7" FT STRAND 1682..1684 FT /evidence="ECO:0007829|PDB:7EA8" FT STRAND 1687..1691 FT /evidence="ECO:0007829|PDB:5LT7" FT HELIX 1697..1700 FT /evidence="ECO:0007829|PDB:5JLB" FT STRAND 2172..2175 FT /evidence="ECO:0007829|PDB:7EVR" FT TURN 2182..2185 FT /evidence="ECO:0007829|PDB:7EVS" FT STRAND 2377..2379 FT /evidence="ECO:0007829|PDB:2MDJ" FT HELIX 2386..2388 FT /evidence="ECO:0007829|PDB:2MDI" FT STRAND 2392..2399 FT /evidence="ECO:0007829|PDB:2MDC" FT TURN 2401..2403 FT /evidence="ECO:0007829|PDB:2MDJ" FT STRAND 2405..2409 FT /evidence="ECO:0007829|PDB:2MDC" FT TURN 2410..2413 FT /evidence="ECO:0007829|PDB:2MDC" FT STRAND 2414..2419 FT /evidence="ECO:0007829|PDB:2MDI" FT STRAND 2424..2428 FT /evidence="ECO:0007829|PDB:2MDC" FT HELIX 2463..2486 FT /evidence="ECO:0007829|PDB:2A7O" FT TURN 2487..2489 FT /evidence="ECO:0007829|PDB:2A7O" FT STRAND 2495..2498 FT /evidence="ECO:0007829|PDB:2A7O" FT HELIX 2502..2524 FT /evidence="ECO:0007829|PDB:2A7O" FT HELIX 2527..2529 FT /evidence="ECO:0007829|PDB:2A7O" FT HELIX 2534..2548 FT /evidence="ECO:0007829|PDB:2A7O" FT TURN 2549..2551 FT /evidence="ECO:0007829|PDB:2A7O" FT HELIX 2557..2559 FT /evidence="ECO:0007829|PDB:2A7O" SQ SEQUENCE 2564 AA; 287597 MW; 2B1BAE5867AB8EAB CRC64; MKQLQPQPPP KMGDFYDPEH PTPEEEENEA KIENVQKTGF IKGPMFKGVA SSRFLPKGTK TKVNLEEQGR QKVSFSFSLT KKTLQNRFLT ALGNEKQSDT PNPPAVPLQV DSTPKMKMEI GDTLSTAEES SPPKSRVELG KIHFKKHLLH VTSRPLLATT TAVASPPTHA APLPAVIAES TTVDSPPSSP PPPPPPAQAT TLSSPAPVTE PVALPHTPIT VLMAAPVPLP VDVAVRSLKE PPIIIVPESL EADTKQDTIS NSLEEHVTQI LNEQADISSK KEDSHIGKDE EIPDSSKISL SCKKTGSKKK SSQSEGIFLG SESDEDSVRT SSSQRSHDLK FSASIEKERD FKKSSAPLKS EDLGKPSRSK TDRDDKYFSY SKLERDTRYV SSRCRSERER RRSRSHSRSE RGSRTNLSYS RSERSHYYDS DRRYHRSSPY RERTRYSRPY TDNRARESSD SEEEYKKTYS RRTSSHSSSY RDLRTSSYSK SDRDCKTETS YLEMERRGKY SSKLERESKR TSENEAIKRC CSPPNELGFR RGSSYSKHDS SASRYKSTLS KPIPKSDKFK NSFCCTELNE EIKQSHSFSL QTPCSKGSEL RMINKNPERE KAGSPAPSNR LNDSPTLKKL DELPIFKSEF ITHDSHDSIK ELDSLSKVKN DQLRSFCPIE LNINGSPGAE SDLATFCTSK TDAVLMTSDD SVTGSELSPL VKACMLSSNG FQNISRCKEK DLDDTCMLHK KSESPFRETE PLVSPHQDKL MSMPVMTVDY SKTVVKEPVD TRVSCCKTKD SDIYCTLNDS NPSLCNSEAE NIEPSVMKIS SNSFMNVHLE SKPVICDSRN LTDHSKFACE EYKQSIGSTS SASVNHFDDL YQPIGSSGIA SSLQSLPPGI KVDSLTLLKC GENTSPVLDA VLKSKKSSEF LKHAGKETIV EVGSDLPDSG KGFASRENRR NNGLSGKCLQ EAQEEGNSIL PERRGRPEIS LDERGEGGHV HTSDDSEVVF SSCDLNLTME DSDGVTYALK CDSSGHAPEI VSTVHEDYSG SSESSNDESD SEDTDSDDSS IPRNRLQSVV VVPKNSTLPM EETSPCSSRS SQSYRHYSDH WEDERLESRR HLYEEKFESI ASKACPQTDK FFLHKGTEKN PEISFTQSSR KQIDNRLPEL SHPQSDGVDS TSHTDVKSDP LGHPNSEETV KAKIPSRQQE ELPIYSSDFE DVPNKSWQQT TFQNRPDSRL GKTELSFSSS CEIPHVDGLH SSEELRNLGW DFSQEKPSTT YQQPDSSYGA CGGHKYQQNA EQYGGTRDYW QGNGYWDPRS GRPPGTGVVY DRTQGQVPDS LTDDREEEEN WDQQDGSHFS DQSDKFLLSL QKDKGSVQAP EISSNSIKDT LAVNEKKDFS KNLEKNDIKD RGPLKKRRQE IESDSESDGE LQDRKKVRVE VEQGETSVPP GSALVGPSCV MDDFRDPQRW KECAKQGKMP CYFDLIEENV YLTERKKNKS HRDIKRMQCE CTPLSKDERA QGEIACGEDC LNRLLMIECS SRCPNGDYCS NRRFQRKQHA DVEVILTEKK GWGLRAAKDL PSNTFVLEYC GEVLDHKEFK ARVKEYARNK NIHYYFMALK NDEIIDATQK GNCSRFMNHS CEPNCETQKW TVNGQLRVGF FTTKLVPSGS ELTFDYQFQR YGKEAQKCFC GSANCRGYLG GENRVSIRAA GGKMKKERSR KKDSVDGELE ALMENGEGLS DKNQVLSLSR LMVRIETLEQ KLTCLELIQN THSQSCLKSF LERHGLSLLW IWMAELGDGR ESNQKLQEEI IKTLEHLPIP TKNMLEESKV LPIIQRWSQT KTAVPPLSEG DGYSSENTSR AHTPLNTPDP STKLSTEADT DTPKKLMFRR LKIISENSMD SAISDATSEL EGKDGKEDLD QLENVPVEEE EELQSQQLLP QQLPECKVDS ETNIEASKLP TSEPEADAEI EPKESNGTKL EEPINEETPS QDEEEGVSDV ESERSQEQPD KTVDISDLAT KLLDSWKDLK EVYRIPKKSQ TEKENTTTER GRDAVGFRDQ TPAPKTPNRS RERDPDKQTQ NKEKRKRRSS LSPPSSAYER GTKRPDDRYD TPTSKKKVRI KDRNKLSTEE RRKLFEQEVA QREAQKQQQQ MQNLGMTSPL PYDSLGYNAP HHPFAGYPPG YPMQAYVDPS NPNAGKVLLP TPSMDPVCSP APYDHAQPLV GHSTEPLSAP PPVPVVPHVA APVEVSSSQY VAQSDGVVHQ DSSVAVLPVP APGPVQGQNY SVWDSNQQSV SVQQQYSPAQ SQATIYYQGQ TCPTVYGVTS PYSQTTPPIV QSYAQPSLQY IQGQQIFTAH PQGVVVQPAA AVTTIVAPGQ PQPLQPSEMV VTNNLLDLPP PSPPKPKTIV LPPNWKTARD PEGKIYYYHV ITRQTQWDPP TWESPGDDAS LEHEAEMDLG TPTYDENPMK ASKKPKTAEA DTSSELAKKS KEVFRKEMSQ FIVQCLNPYR KPDCKVGRIT TTEDFKHLAR KLTHGVMNKE LKYCKNPEDL ECNENVKHKT KEYIKKYMQK FGAVYKPKED TELE //