ID   MLL5_MOUSE              Reviewed;        1868 AA.
AC   Q3UG20; Q3SYI5; Q3TUY2; Q3V410; Q5FWI1; Q6P3B3; Q8BS65; Q8CFX7;
AC   Q9CVK6;
DT   10-JUN-2008, integrated into UniProtKB/Swiss-Prot.
DT   10-JUN-2008, sequence version 2.
DT   07-JUL-2009, entry version 32.
DE   RecName: Full=Histone-lysine N-methyltransferase MLL5;
DE            EC=2.1.1.43;
DE   AltName: Full=Myeloid/lymphoid or mixed-lineage leukemia protein 5 homolog;
GN   Name=Mll5;
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Sciurognathi;
OC   Muroidea; Muridae; Murinae; Mus.
OX   NCBI_TaxID=10090;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=C57BL/6J;
RG   The mouse genome sequencing consortium;
RL   Submitted (NOV-2003) to the EMBL/GenBank/DDBJ databases.
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-1153 (ISOFORM 1).
RC   STRAIN=C57BL/6J;
RC   TISSUE=Embryo, Embryonic eye, Melanoma, Pancreas, and Tongue;
RX   PubMed=16141072; DOI=10.1126/science.1112014;
RA   Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA   Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA   Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M.,
RA   Davis M.J., Wilming L.G., Aidinis V., Allen J.E.,
RA   Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L.,
RA   Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M.,
RA   Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R.,
RA   Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G.,
RA   di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G.,
RA   Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M.,
RA   Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA   Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N.,
RA   Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T.,
RA   Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H.,
RA   Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K.,
RA   Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J.,
RA   Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L.,
RA   Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K.,
RA   Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P.,
RA   Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O.,
RA   Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G.,
RA   Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M.,
RA   Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA   Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA   Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B.,
RA   Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K.,
RA   Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A.,
RA   Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K.,
RA   Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C.,
RA   Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J.,
RA   Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y.,
RA   Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T.,
RA   Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N.,
RA   Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N.,
RA   Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S.,
RA   Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J.,
RA   Hayashizaki Y.;
RT   "The transcriptional landscape of the mammalian genome.";
RL   Science 309:1559-1563(2005).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-802 (ISOFORM 2), AND
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-494 (ISOFORM 1).
RC   STRAIN=C57BL/6, C57BL/6J, and FVB/N;
RC   TISSUE=Eye, Mammary gland, and Mammary tumor;
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
RT   project: the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [4]
RP   INDUCTION.
RX   PubMed=18376068; DOI=10.1007/s12038-008-0019-6;
RA   Sambasivan R., Pavlath G.K., Dhawan J.;
RT   "A gene-trap strategy identifies quiescence-induced genes in
RT   synchronized myoblasts.";
RL   J. Biosci. 33:27-44(2008).
RN   [5]
RP   FUNCTION, AND DISRUPTION PHENOTYPE.
RX   PubMed=18854576; DOI=10.1182/blood-2008-06-162263;
RA   Heuser M., Yap D.B., Leung M., de Algara T.R., Tafech A., McKinney S.,
RA   Dixon J., Thresher R., Colledge B., Carlton M., Humphries R.K.,
RA   Aparicio S.A.;
RT   "Loss of MLL5 results in pleiotropic hematopoietic defects, reduced
RT   neutrophil immune function, and extreme sensitivity to DNA
RT   demethylation.";
RL   Blood 113:1432-1443(2009).
RN   [6]
RP   FUNCTION, AND DISRUPTION PHENOTYPE.
RX   PubMed=18952892; DOI=10.1182/blood-2008-02-142638;
RA   Madan V., Madan B., Brykczynska U., Zilbermann F., Hogeveen K.,
RA   Doehner K., Doehner H., Weber O., Blum C., Rodewald H.-R.,
RA   Sassone-Corsi P., Peters A.H.F.M., Fehling H.J.;
RT   "Impaired function of primitive hematopoietic cells in mice lacking
RT   the Mixed-Lineage-Leukemia homolog MLL5.";
RL   Blood 113:1444-1454(2009).
RN   [7]
RP   FUNCTION, AND DISRUPTION PHENOTYPE.
RX   PubMed=18818388; DOI=10.1182/blood-2008-05-159905;
RA   Zhang Y., Wong J., Klinger M., Tran M.T., Shannon K.M., Killeen N.;
RT   "MLL5 contributes to hematopoietic stem cell fitness and
RT   homeostasis.";
RL   Blood 113:1455-1463(2009).
RN   [8]
RP   FUNCTION, AND MUTAGENESIS OF CYS-411.
RX   PubMed=19264965; DOI=10.1073/pnas.0807136106;
RA   Sebastian S., Sreenivas P., Sambasivan R., Cheedipudi S., Kandalla P.,
RA   Pavlath G.K., Dhawan J.;
RT   "MLL5, a trithorax homolog, indirectly regulates H3K4 methylation,
RT   represses cyclin A2 expression, and promotes myogenic
RT   differentiation.";
RL   Proc. Natl. Acad. Sci. U.S.A. 106:4719-4724(2009).
CC   -!- FUNCTION: Histone methyltransferase that specifically mono- and
CC       dimethylates 'Lys-4' of histone H3 (H3K4me1 and H3K4me2). H3 'Lys-
CC       4' methylation represents a specific tag for epigenetic
CC       transcriptional activation. Key regulator of hematopoiesis
CC       involved in terminal myeloid differentiation and in the regulation
CC       of hematopoietic stem cell (HSCs) self-renewal by a mechanism that
CC       involves DNA methylation. Plays an essential role in retinoic-
CC       acid-induced granulopoiesis by acting as a coactivator of RAR-
CC       alpha (RARA) in target gene promoters. Also acts as an important
CC       cell cycle regulator, participating in cell cycle regulatory
CC       network machinery at multiple cell cycle stages. Required to
CC       suppress inappropriate expression of S-phase-promoting genes and
CC       maintain expression of determination genes in quiescent cells.
CC       Overexpression inhibits cell cycle progression, while knockdown
CC       induces cell cycle arrest at both the G1 and G2/M phases.
CC   -!- CATALYTIC ACTIVITY: S-adenosyl-L-methionine + histone L-lysine =
CC       S-adenosyl-L-homocysteine + histone N(6)-methyl-L-lysine.
CC   -!- SUBUNIT: Component of the MLL5-L complex, at least composed of
CC       MLL5, STK38, PPP1CA, PPP1CB, PPP1CC, HCFC1, ACTB and OGT.
CC       Interacts with RARA (By similarity).
CC   -!- SUBCELLULAR LOCATION: Nucleus speckle (By similarity). Note=Absent
CC       from the nucleolus (By similarity).
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q3UG20-1; Sequence=Displayed;
CC         Note=No experimental confirmation available;
CC       Name=2;
CC         IsoId=Q3UG20-2; Sequence=VSP_052813;
CC         Note=No experimental confirmation available;
CC   -!- INDUCTION: Up-regulated in reversibly arrested C2C12 myoblasts.
CC   -!- PTM: O-glycosylation at Thr-440 in the SET domain by OGT is
CC       essential for the histone methyltransferase and the coactivator
CC       activity toward RARA in granulopoiesis (By similarity). The
CC       absence of Thr-440 glycosylation in assays done in vitro may
CC       explain why PubMed:18952892 and PubMed:19264965 did not detected
CC       any histone methyltransferase activity for this protein.
CC   -!- DISRUPTION PHENOTYPE: Defects in immunity and hematopoiesis. Adult
CC       homozygous mice are obtained at reduced frequency because of
CC       postnatal lethality. Surviving animals display a variety of
CC       abnormalities, including male infertility, retarded growth and
CC       defects in multiple hematopoietic lineages. They also show
CC       increased susceptibility to spontaneous eye infections associated
CC       with a cell-autonomous impairment of neutrophil function. They
CC       exhibit a mild impairment of erythropoiesis and hematopoietic stem
CC       cells (HSCs) have impaired competitive repopulating capacity both
CC       under normal conditions and when subjected to self-renewal
CC       stimulation by NUP98-HOXA10. Homozygous HSCs show a dramatic
CC       sensitivity to DNA demethylation-induced differentiation (5-
CC       azadeoxycytidine).
CC   -!- SIMILARITY: Belongs to the histone-lysine methyltransferase
CC       family. TRX/MLL subfamily.
CC   -!- SIMILARITY: Contains 1 PHD-type zinc finger.
CC   -!- SIMILARITY: Contains 1 SET domain.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAH36286.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence starting in position 486;
CC       Sequence=AAH64079.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence starting in position 803;
CC       Sequence=AAH89356.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence starting in position 495;
CC       Sequence=AAI03802.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence starting in position 492;
CC       Sequence=BAE28389.1; Type=Frameshift; Positions=12;
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DR   EMBL; AC122022; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AK007682; BAB25186.1; ALT_INIT; mRNA.
DR   EMBL; AK021284; BAE43262.1; -; mRNA.
DR   EMBL; AK035078; BAC28936.2; ALT_INIT; mRNA.
DR   EMBL; AK148169; BAE28389.1; ALT_FRAME; mRNA.
DR   EMBL; AK160519; BAE35839.1; -; mRNA.
DR   EMBL; BC036286; AAH36286.1; ALT_SEQ; mRNA.
DR   EMBL; BC064079; AAH64079.1; ALT_SEQ; mRNA.
DR   EMBL; BC089356; AAH89356.1; ALT_SEQ; mRNA.
DR   EMBL; BC103801; AAI03802.1; ALT_SEQ; mRNA.
DR   IPI; IPI00660988; -.
DR   IPI; IPI00896088; -.
DR   UniGene; Mm.205190; -.
DR   UniGene; Mm.403814; -.
DR   UniGene; Mm.471659; -.
DR   PhosphoSite; Q3UG20; -.
DR   Ensembl; ENSMUSG00000029004; Mus musculus.
DR   MGI; MGI:1924825; Mll5.
DR   HOGENOM; Q3UG20; -.
DR   HOVERGEN; Q3UG20; -.
DR   OMA; Q3UG20; PGHHVTP.
DR   ArrayExpress; Q3UG20; -.
DR   Bgee; Q3UG20; -.
DR   GO; GO:0035097; C:histone methyltransferase complex; ISS:UniProtKB.
DR   GO; GO:0016607; C:nuclear speck; IEA:UniProtKB-SubCell.
DR   GO; GO:0042800; F:histone methyltransferase activity (H3-K4 s...; ISS:UniProtKB.
DR   GO; GO:0003713; F:transcription coactivator activity; ISS:UniProtKB.
DR   GO; GO:0008270; F:zinc ion binding; IEA:UniProtKB-KW.
DR   GO; GO:0007050; P:cell cycle arrest; IEA:UniProtKB-KW.
DR   GO; GO:0006306; P:DNA methylation; IMP:UniProtKB.
DR   GO; GO:0030218; P:erythrocyte differentiation; IMP:UniProtKB.
DR   GO; GO:0016571; P:histone methylation; ISS:UniProtKB.
DR   GO; GO:0042119; P:neutrophil activation; IMP:UniProtKB.
DR   GO; GO:0002446; P:neutrophil mediated immunity; IMP:UniProtKB.
DR   GO; GO:0045893; P:positive regulation of transcription, DNA-d...; ISS:UniProtKB.
DR   GO; GO:0032526; P:response to retinoic acid; ISS:UniProtKB.
DR   GO; GO:0048384; P:retinoic acid receptor signaling pathway; ISS:UniProtKB.
DR   InterPro; IPR001214; SET.
DR   InterPro; IPR019786; Zinc_finger_PHD-type_CS.
DR   InterPro; IPR001965; Znf_PHD.
DR   InterPro; IPR019787; Znf_PHD-finger.
DR   Pfam; PF00628; PHD; 1.
DR   Pfam; PF00856; SET; 1.
DR   SMART; SM00249; PHD; 1.
DR   SMART; SM00317; SET; 1.
DR   PROSITE; PS50280; SET; 1.
DR   PROSITE; PS01359; ZF_PHD_1; 1.
DR   PROSITE; PS50016; ZF_PHD_2; 1.
PE   1: Evidence at protein level;
KW   Alternative splicing; Cell cycle; Chromatin regulator; Coiled coil;
KW   Glycoprotein; Growth arrest; Metal-binding; Methyltransferase;
KW   Nucleus; Phosphoprotein; S-adenosyl-L-methionine; Transcription;
KW   Transcription regulation; Transferase; Zinc; Zinc-finger.
FT   CHAIN         1   1868       Histone-lysine N-methyltransferase MLL5.
FT                                /FTId=PRO_0000341420.
FT   DOMAIN      328    451       SET.
FT   ZN_FING     118    166       PHD-type.
FT   COILED      559    613       Potential.
FT   COMPBIAS   1549   1856       Pro-rich.
FT   MOD_RES    1410   1410       Phosphoserine (By similarity).
FT   CARBOHYD    440    440       O-linked (GalNAc...) (By similarity).
FT   VAR_SEQ       1    580       Missing (in isoform 2).
FT                                /FTId=VSP_052813.
FT   MUTAGEN     411    411       C->A: Unable to repress cell-cycle-
FT                                regulated element.
FT   CONFLICT     62     62       A -> S (in Ref. 2; BAE43262).
FT   CONFLICT    181    181       R -> I (in Ref. 2; BAE28389).
FT   CONFLICT    320    320       E -> G (in Ref. 2; BAE28389).
FT   CONFLICT    489    489       R -> S (in Ref. 2; BAB25186).
FT   CONFLICT    512    512       D -> Y (in Ref. 2; BAC28936).
FT   CONFLICT    550    550       E -> G (in Ref. 2; BAE35839).
FT   CONFLICT    562    562       E -> G (in Ref. 2; BAE28389).
FT   CONFLICT   1005   1005       S -> R (in Ref. 2; BAC28936).
SQ   SEQUENCE   1868 AA;  204543 MW;  B676F509E965415C CRC64;
     MSIAIPLGVD TTETSYLEMA AGSEPESVEA SPVVVEKSNS FPHQLYTSSS HHSHSYIGLP
     YADHNYGARP PPTPPASPPP SGLISKNEVG IFTTPNFDET SSATTISTSE DGSYGTDVTR
     CICGFTHDDG YMICCDKCSV WQHIDCMGID RQHIPDTYLC ERCQPRSLDK ERAVLLQRRK
     RENMSDGDTS ATESGDEVPV ELYTAFQHTP TSITLTASRV PKVTDKRRKK SGEKEQNFSK
     CKKAFREGSR KSSRVKGSAP EIDPSSDSSN FVWETKIKAW MDRYEEANNN QYSEGVQREA
     QRLAQRLGSG NDSKDMNKSE LSTNNSLFRP PVESHIQKNK KILKSAKDLP PDALIIEYRG
     KFMLREQFEA NGYFFKRPYP FVLFYSKFHG LEMCVDARTF GNEARFIRRS CTPNAEVRHE
     IEEGTIHLYI YSIQSIPKGT EITIAFDFDY GNCKYKVDCA CLKENPECPV LKRSSESTEN
     INSGYETRRK KGKKEKDTSK EKDIQNQNMT LDCEGTNNKI RSPETKQRKL SPLRLSVSNN
     QEPDFIDDME EKTPISNEVE MESEEQIAER KRKMTREERK MEAILQAFAR LEKREKRREQ
     ALERISTAKT EVKPECKESQ VIADAEVVQE QVKEETAIKP AAAKVNRTKQ RKSFSRSRTH
     IGQQRRRHRT VSMCSDIPPS SPDIEVLSQQ NEIENTVLAI EPETETAVAE IIPEAEVPAL
     NKCPTKYPKT KKHLVNEWLS EKNEKTGKPS DSLSERPLRI TTDPEVLATQ LNSLPGLTYS
     PHVYSTPKHY IRFTSPFLSE KKRRKETTEN ISGSCKKRWL KQALEEENST ILHRYHSPCQ
     ERSRSPTVNG ENKSPLLLSD SCSLPDLTTP LKKRRLYQLL DTAYSESSTP TPSPYATPTH
     TDITPTDPAF ATPPRIKSDD ETYRNGYKPI YSPVTPVTPG TPGNTMHFEN ISSPESSPEI
     KRCTYNQEGY DRPSNMLTLG PFRNSNLTEL GLQEIKTIGY TSPRSRTEVN RPCPGEKESV
     SDLQLGLDAV EPAALQKSME TPAHDRTEPS NQLDSTHSGR GTMYSSWVKS PDRTGVNFSV
     NSNLRDLTPS HQLETGGGFR VSESKCLIQQ DDTRGMFLGA AVFCTSEDGL ASGFGRTVND
     NLIDGSCTPQ NPPQKKKVSL LEYRKRQREA RKSGSKPENF ALISVSPHPS GSLSSSGDGC
     VHSSENGEQA ENQASLPLPP PAAAAAATAA AAYSASSEEG SSNCPVKDAN SSEKKDPEVQ
     WTASTSVEQV RERSYQRALL LSDHRKDKDS GGESPCVSCS PSHVQSPPSS HSNHIPQVHA
     QSLAPSLSEL MADPDAEGTE ATSTSECPSP DTSQSPSKTS KPGSPGPINP AQSHGKILTK
     PDSHWEATAT VSEADNSVHQ NPEPQHRQLS SNTPALSQNH APQAHALSAN DQLPQKLPSA
     PTKLHCPPSP HTENPPKSST PHTPVQHGYL SPKPPSQHLG SPFRPHHSQS PQVGTPQRET
     QRNFYAAAQN LQANPQQATS GALFTQTPSG QSSATYSQFN QQSLNSTAPP PPPPPPPSSY
     YQNQQPSANF QNYNQLKGSL SQQTVFTSGP NQALPGSTSQ QSVPGHHVTP GHFLPSQNPT
     IHHQPAAAAV VPPPPPPPPA PGPHLIQQPS SHQQHSVAHG VGPVHAVTPG SHIHSQTAGH
     HLPPPPPPPG PAPHHHPPPH PTTGLQSLQA QHQHVVNSAP PPPPPPPPPP PASVLVSGHH
     SASGQALHHP PHQGPPLFPA SAHPAVPPYP SQATHHTTLG PGPQHQPSGT GPHCPLPVAG
     PHLQPQGPNS IPTPTASGFC PHPHPGSVAL PHGVQGPQQA SPVPAQIPIH RAQVPPTFQN
     NYHGSGWH
//