ID XRCC4_HUMAN Reviewed; 336 AA. AC Q13426; A8K3X4; Q9BS72; Q9UP94; DT 01-MAR-2004, integrated into UniProtKB/Swiss-Prot. DT 01-MAR-2004, sequence version 2. DT 24-JAN-2024, entry version 207. DE RecName: Full=DNA repair protein XRCC4 {ECO:0000305}; DE Short=hXRCC4 {ECO:0000303|PubMed:14599745}; DE AltName: Full=X-ray repair cross-complementing protein 4 {ECO:0000303|PubMed:8548796}; DE Contains: DE RecName: Full=Protein XRCC4, C-terminus {ECO:0000305|PubMed:33725486}; DE Short=XRCC4/C {ECO:0000303|PubMed:33725486}; GN Name=XRCC4 {ECO:0000303|PubMed:8548796, ECO:0000312|HGNC:HGNC:12831}; 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 [MRNA] (ISOFORM 2), FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=8548796; DOI=10.1016/0092-8674(95)90135-3; RA Li Z., Otevrel T., Gao Y., Cheng H.L., Seed B., Stamato T.D., RA Taccioli G.E., Alt F.W.; RT "The XRCC4 gene encodes a novel protein involved in DNA double-strand break RT repair and V(D)J recombination."; RL Cell 83:1079-1089(1995). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RA Fugmann S.D., Schwarz K.; RT "The genomic structure of the human XRCC4 gene."; RL Submitted (MAR-1998) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RA Tatsumi K.; RT "Human lymphoblastoid cell line TK-6 lacking in a novel component involved RT in V(D)J recombination."; RL Submitted (SEP-1998) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3). RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."; RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). 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 [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS CYS-12; THR-56; THR-134; RP GLN-142 AND SER-247. RG NIEHS SNPs program; RL Submitted (FEB-2005) to the EMBL/GenBank/DDBJ databases. RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3). RC TISSUE=Bone marrow; 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 [9] RP INTERACTION WITH LIG4, PHOSPHORYLATION, AND SUBCELLULAR LOCATION. RX PubMed=9259561; DOI=10.1016/s0960-9822(06)00258-2; RA Critchlow S.E., Bowater R.P., Jackson S.P.; RT "Mammalian DNA double-strand break repair protein XRCC4 interacts with DNA RT ligase IV."; RL Curr. Biol. 7:588-598(1997). RN [10] RP PHOSPHORYLATION BY PRKDC. RX PubMed=9430729; DOI=10.1074/jbc.273.3.1794; RA Leber R., Wise T.W., Mizuta R., Meek K.; RT "The XRCC4 gene product is a target for and interacts with the DNA- RT dependent protein kinase."; RL J. Biol. Chem. 273:1794-1801(1998). RN [11] RP PHOSPHORYLATION AT SER-260 AND SER-320. RX PubMed=15177042; DOI=10.1016/j.dnarep.2003.11.005; RA Lee K.J., Jovanovic M., Udayakumar D., Bladen C.L., Dynan W.S.; RT "Identification of DNA-PKcs phosphorylation sites in XRCC4 and effects of RT mutations at these sites on DNA end joining in a cell-free system."; RL DNA Repair 3:267-276(2004). RN [12] RP FUNCTION, AND INTERACTION WITH LIG4. RX PubMed=9242410; DOI=10.1038/41358; RA Grawunder U., Wilm M., Wu X., Kulesza P., Wilson T.E., Mann M., RA Lieber M.R.; RT "Activity of DNA ligase IV stimulated by complex formation with XRCC4 RT protein in mammalian cells."; RL Nature 388:492-495(1997). RN [13] RP PROTEOLYTIC CLEAVAGE, AND PHOSPHORYLATION. RX PubMed=10922471; DOI=10.1016/s0014-5793(00)01800-7; RA Matsumoto Y., Suzuki N., Namba N., Umeda N., Ma X.J., Morita A., Tomita M., RA Enomoto A., Serizawa S., Hirano K., Sakaia K., Yasuda H., Hosoi Y.; RT "Cleavage and phosphorylation of XRCC4 protein induced by X-irradiation."; RL FEBS Lett. 478:67-71(2000). RN [14] RP FUNCTION, AND INTERACTION WITH LIG4; XRCC6; XRCC5 AND PRKDC. RX PubMed=10854421; DOI=10.1074/jbc.m000491200; RA Chen L., Trujillo K., Sung P., Tomkinson A.E.; RT "Interactions of the DNA ligase IV-XRCC4 complex with DNA ends and the DNA- RT dependent protein kinase."; RL J. Biol. Chem. 275:26196-26205(2000). RN [15] RP FUNCTION, AND INTERACTION WITH XRCC6 AND XRCC5. RX PubMed=10757784; DOI=10.1128/mcb.20.9.2996-3003.2000; RA Nick McElhinny S.A., Snowden C.M., McCarville J., Ramsden D.A.; RT "Ku recruits the XRCC4-ligase IV complex to DNA ends."; RL Mol. Cell. Biol. 20:2996-3003(2000). RN [16] RP INTERACTION WITH PRKDC. RX PubMed=12509254; DOI=10.1016/s1568-7864(01)00018-0; RA Hsu H.-L., Yannone S.M., Chen D.J.; RT "Defining interactions between DNA-PK and ligase IV/XRCC4."; RL DNA Repair 1:225-235(2002). RN [17] RP FUNCTION, AND INTERACTION WITH LIG4. RX PubMed=12517771; RA Lee J.W., Yannone S.M., Chen D.J., Povirk L.F.; RT "Requirement for XRCC4 and DNA ligase IV in alignment-based gap filling for RT nonhomologous DNA end joining in vitro."; RL Cancer Res. 63:22-24(2003). RN [18] RP PHOSPHORYLATION AT SER-53; SER-193; SER-260; SER-303; SER-315; SER-320; RP THR-323; SER-327 AND SER-328, AND MUTAGENESIS OF SER-260 AND SER-320. RX PubMed=14599745; DOI=10.1016/s1568-7864(03)00143-5; RA Yu Y., Wang W., Ding Q., Ye R., Chen D., Merkle D., Schriemer D., Meek K., RA Lees-Miller S.P.; RT "DNA-PK phosphorylation sites in XRCC4 are not required for survival after RT radiation or for V(D)J recombination."; RL DNA Repair 2:1239-1252(2003). RN [19] RP IDENTIFICATION IN A COMPLEX WITH XRCC6; XRCC5 AND PRKDC, AND RP PHOSPHORYLATION. RX PubMed=12547193; DOI=10.1016/s0022-2836(02)01328-1; RA Calsou P., Delteil C., Frit P., Drouet J., Salles B.; RT "Coordinated assembly of Ku and p460 subunits of the DNA-dependent protein RT kinase on DNA ends is necessary for XRCC4-ligase IV recruitment."; RL J. Mol. Biol. 326:93-103(2003). RN [20] RP INTERACTION WITH APTX, AND PHOSPHORYLATION. RX PubMed=15380105; DOI=10.1016/j.dnarep.2004.06.017; RA Clements P.M., Breslin C., Deeks E.D., Byrd P.J., Ju L., Bieganowski P., RA Brenner C., Moreira M.-C., Taylor A.M.R., Caldecott K.W.; RT "The ataxia-oculomotor apraxia 1 gene product has a role distinct from ATM RT and interacts with the DNA strand break repair proteins XRCC1 and XRCC4."; RL DNA Repair 3:1493-1502(2004). RN [21] RP FUNCTION, PHOSPHORYLATION AT THR-233, INTERACTION WITH PNKP, AND RP MUTAGENESIS OF THR-233; THR-264; THR-282; THR-308 AND THR-323. RX PubMed=15385968; DOI=10.1038/sj.emboj.7600375; RA Koch C.A., Agyei R., Galicia S., Metalnikov P., O'Donnell P., RA Starostine A., Weinfeld M., Durocher D.; RT "Xrcc4 physically links DNA end processing by polynucleotide kinase to DNA RT ligation by DNA ligase IV."; RL EMBO J. 23:3874-3885(2004). RN [22] RP MONOUBIQUITINATION, PHOSPHORYLATION, AND FUNCTION. RX PubMed=16412978; DOI=10.1016/j.bbrc.2005.12.166; RA Foster R.E., Nnakwe C., Woo L., Frank K.M.; RT "Monoubiquitination of the nonhomologous end joining protein XRCC4."; RL Biochem. Biophys. Res. Commun. 341:175-183(2006). RN [23] RP INTERACTION WITH NHEJ1. RX PubMed=16439205; DOI=10.1016/j.cell.2005.12.031; RA Ahnesorg P., Smith P., Jackson S.P.; RT "XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA RT nonhomologous end-joining."; RL Cell 124:301-313(2006). RN [24] RP FUNCTION, AND INTERACTION WITH XRCC6. RX PubMed=17124166; DOI=10.1073/pnas.0609061103; RA Mari P.O., Florea B.I., Persengiev S.P., Verkaik N.S., Brueggenwirth H.T., RA Modesti M., Giglia-Mari G., Bezstarosti K., Demmers J.A., Luider T.M., RA Houtsmuller A.B., van Gent D.C.; RT "Dynamic assembly of end-joining complexes requires interaction between RT Ku70/80 and XRCC4."; RL Proc. Natl. Acad. Sci. U.S.A. 103:18597-18602(2006). RN [25] RP SUMOYLATION AT LYS-210, SUBCELLULAR LOCATION, AND MUTAGENESIS OF LYS-140 RP AND LYS-210. RX PubMed=16478998; DOI=10.1128/mcb.26.5.1786-1794.2006; RA Yurchenko V., Xue Z., Sadofsky M.J.; RT "SUMO modification of human XRCC4 regulates its localization and function RT in DNA double-strand break repair."; RL Mol. Cell. Biol. 26:1786-1794(2006). RN [26] RP FUNCTION, AND INTERACTION WITH LIG4. RX PubMed=17290226; DOI=10.1038/sj.emboj.7601559; RA Gu J., Lu H., Tippin B., Shimazaki N., Goodman M.F., Lieber M.R.; RT "XRCC4:DNA ligase IV can ligate incompatible DNA ends and can ligate across RT gaps."; RL EMBO J. 26:1010-1023(2007). RN [27] RP INTERACTION WITH NHEJ1, AND MUTAGENESIS OF LYS-4; LYS-26; LYS-65; ARG-71; RP LYS-72; LYS-99 AND LYS-102. RX PubMed=18158905; DOI=10.1016/j.molcel.2007.10.024; RA Andres S.N., Modesti M., Tsai C.J., Chu G., Junop M.S.; RT "Crystal structure of human XLF: a twist in nonhomologous DNA end- RT joining."; RL Mol. Cell 28:1093-1101(2007). RN [28] RP INTERACTION WITH APLF. RX PubMed=17396150; DOI=10.1038/sj.emboj.7601663; RA Kanno S., Kuzuoka H., Sasao S., Hong Z., Lan L., Nakajima S., Yasui A.; RT "A novel human AP endonuclease with conserved zinc-finger-like motifs RT involved in DNA strand break responses."; RL EMBO J. 26:2094-2103(2007). RN [29] RP INTERACTION WITH APLF. RX PubMed=17353262; DOI=10.1128/mcb.02269-06; RA Iles N., Rulten S., El-Khamisy S.F., Caldecott K.W.; RT "APLF (C2orf13) is a novel human protein involved in the cellular response RT to chromosomal DNA strand breaks."; RL Mol. Cell. Biol. 27:3793-3803(2007). RN [30] RP INTERACTION WITH APLF. RX PubMed=18077224; DOI=10.1016/j.dnarep.2007.10.008; RA Macrae C.J., McCulloch R.D., Ylanko J., Durocher D., Koch C.A.; RT "APLF (C2orf13) facilitates nonhomologous end-joining and undergoes ATM- RT dependent hyperphosphorylation following ionizing radiation."; RL DNA Repair 7:292-302(2008). RN [31] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-327 AND SER-328, AND RP IDENTIFICATION BY 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 [32] RP INTERACTION WITH LIG4. RX PubMed=19837014; DOI=10.1016/j.dnarep.2009.09.007; RA Recuero-Checa M.A., Dore A.S., Arias-Palomo E., Rivera-Calzada A., RA Scheres S.H., Maman J.D., Pearl L.H., Llorca O.; RT "Electron microscopy of Xrcc4 and the DNA ligase IV-Xrcc4 DNA repair RT complex."; RL DNA Repair 8:1380-1389(2009). RN [33] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-327 AND SER-328, AND RP IDENTIFICATION BY MASS SPECTROMETRY [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 [34] RP INTERACTION WITH NHEJ1. RX PubMed=20558749; DOI=10.1074/jbc.m110.138156; RA Malivert L., Ropars V., Nunez M., Drevet P., Miron S., Faure G., RA Guerois R., Mornon J.P., Revy P., Charbonnier J.B., Callebaut I., RA de Villartay J.P.; RT "Delineation of the Xrcc4-interacting region in the globular head domain of RT cernunnos/XLF."; RL J. Biol. Chem. 285:26475-26483(2010). RN [35] RP FUNCTION, PHOSPHORYLATION AT THR-233, AND INTERACTION WITH PNKP. RX PubMed=20852255; DOI=10.1074/jbc.m109.058719; RA Mani R.S., Yu Y., Fang S., Lu M., Fanta M., Zolner A.E., Tahbaz N., RA Ramsden D.A., Litchfield D.W., Lees-Miller S.P., Weinfeld M.; RT "Dual modes of interaction between XRCC4 and polynucleotide RT kinase/phosphatase: implications for nonhomologous end joining."; RL J. Biol. Chem. 285:37619-37629(2010). RN [36] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-256, AND IDENTIFICATION BY RP 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 [37] RP CRYSTALLIZATION. RX PubMed=22102241; DOI=10.1107/s1744309111033549; RA Andres S.N., Junop M.S.; RT "Crystallization and preliminary X-ray diffraction analysis of the human RT XRCC4-XLF complex."; RL Acta Crystallogr. F 67:1399-1402(2011). RN [38] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [39] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH LIG4. RX PubMed=21982441; DOI=10.1016/j.dnarep.2011.09.012; RA Berg E., Christensen M.O., Dalla Rosa I., Wannagat E., Jaenicke R.U., RA Roesner L.M., Dirks W.G., Boege F., Mielke C.; RT "XRCC4 controls nuclear import and distribution of Ligase IV and exchanges RT faster at damaged DNA in complex with Ligase IV."; RL DNA Repair 10:1232-1242(2011). RN [40] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE 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 [41] RP FUNCTION, INTERACTION WITH NHEJ1, AND PHOSPHORYLATION AT SER-193; SER-260; RP SER-303; SER-315; SER-320; THR-323; SER-327 AND SER-328. RX PubMed=22228831; DOI=10.1093/nar/gkr1315; RA Roy S., Andres S.N., Vergnes A., Neal J.A., Xu Y., Yu Y., Lees-Miller S.P., RA Junop M., Modesti M., Meek K.; RT "XRCC4's interaction with XLF is required for coding (but not signal) end RT joining."; RL Nucleic Acids Res. 40:1684-1694(2012). RN [42] RP INTERACTION WITH LIG4 AND NHEJ1. RX PubMed=22658747; DOI=10.1016/j.str.2012.04.012; RA Ochi T., Wu Q., Chirgadze D.Y., Grossmann J.G., Bolanos-Garcia V.M., RA Blundell T.L.; RT "Structural insights into the role of domain flexibility in human DNA RT ligase IV."; RL Structure 20:1212-1222(2012). RN [43] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-260; SER-304 AND SER-320, AND RP 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 [44] RP SUBCELLULAR LOCATION, AND INTERACTION WITH LIG4. RX PubMed=24984242; DOI=10.1016/j.dnarep.2014.05.010; RA Francis D.B., Kozlov M., Chavez J., Chu J., Malu S., Hanna M., Cortes P.; RT "DNA Ligase IV regulates XRCC4 nuclear localization."; RL DNA Repair 21:36-42(2014). RN [45] RP INVOLVEMENT IN SSMED, AND VARIANT SSMED ARG-43. RX PubMed=24389050; DOI=10.1101/gr.160572.113; RA Shaheen R., Faqeih E., Ansari S., Abdel-Salam G., Al-Hassnan Z.N., RA Al-Shidi T., Alomar R., Sogaty S., Alkuraya F.S.; RT "Genomic analysis of primordial dwarfism reveals novel disease genes."; RL Genome Res. 24:291-299(2014). RN [46] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-229; THR-233 AND SER-237, AND RP 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 [47] RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF GLU-235; GLU-322; RP THR-323; LEU-324; ASN-326; SER-327; SER-328; PRO-329; GLU-330; ASP-331; RP LEU-332; PHE-333 AND ASP-334. RX PubMed=25597996; DOI=10.1016/j.bbrc.2015.01.015; RA Wanotayan R., Fukuchi M., Imamichi S., Sharma M.K., Matsumoto Y.; RT "Asparagine 326 in the extremely C-terminal region of XRCC4 is essential RT for the cell survival after irradiation."; RL Biochem. Biophys. Res. Commun. 457:526-531(2015). RN [48] RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH LIG4, NUCLEAR LOCALIZATION RP SIGNAL, AND MUTAGENESIS OF LYS-210 AND LYS-271. RX PubMed=25934149; DOI=10.1016/j.bbrc.2015.04.093; RA Fukuchi M., Wanotayan R., Liu S., Imamichi S., Sharma M.K., Matsumoto Y.; RT "Lysine 271 but not lysine 210 of XRCC4 is required for the nuclear RT localization of XRCC4 and DNA ligase IV."; RL Biochem. Biophys. Res. Commun. 461:687-694(2015). RN [49] RP SUBUNIT. RX PubMed=25941166; DOI=10.1038/cdd.2015.22; RA Craxton A., Somers J., Munnur D., Jukes-Jones R., Cain K., Malewicz M.; RT "XLS (c9orf142) is a new component of mammalian DNA double-stranded break RT repair."; RL Cell Death Differ. 22:890-897(2015). RN [50] RP FUNCTION, AND INTERACTION WITH NHEJ1. RX PubMed=26100018; DOI=10.1128/mcb.01503-14; RA Roy S., de Melo A.J., Xu Y., Tadi S.K., Negrel A., Hendrickson E., RA Modesti M., Meek K.; RT "XRCC4/XLF interaction is variably required for DNA repair and is not RT required for ligase IV stimulation."; RL Mol. Cell. Biol. 35:3017-3028(2015). RN [51] RP SUBUNIT. RX PubMed=25670504; DOI=10.1038/ncomms7233; RA Xing M., Yang M., Huo W., Feng F., Wei L., Jiang W., Ning S., Yan Z., RA Li W., Wang Q., Hou M., Dong C., Guo R., Gao G., Ji J., Zha S., Lan L., RA Liang H., Xu D.; RT "Interactome analysis identifies a new paralogue of XRCC4 in non-homologous RT end joining DNA repair pathway."; RL Nat. Commun. 6:6233-6233(2015). RN [52] RP SUBUNIT. RX PubMed=25574025; DOI=10.1126/science.1261971; RA Ochi T., Blackford A.N., Coates J., Jhujh S., Mehmood S., Tamura N., RA Travers J., Wu Q., Draviam V.M., Robinson C.V., Blundell T.L., RA Jackson S.P.; RT "DNA repair. PAXX, a paralog of XRCC4 and XLF, interacts with Ku to promote RT DNA double-strand break repair."; RL Science 347:185-188(2015). RN [53] RP PHOSPHORYLATION AT SER-320. RX PubMed=26666690; DOI=10.1093/jrr/rrv086; RA Sharma M.K., Imamichi S., Fukuchi M., Samarth R.M., Tomita M., RA Matsumoto Y.; RT "In cellulo phosphorylation of XRCC4 Ser320 by DNA-PK induced by DNA RT damage."; RL J. Radiat. Res. 57:115-120(2016). RN [54] RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH XRCC5 AND XRCC6, RP PHOSPHORYLATION AT SER-327 AND SER-328, UBIQUITINATION AT LYS-296, AND RP MUTAGENESIS OF LYS-271; LYS-285; LYS-296; THR-308 AND 327-SER-SER-328. RX PubMed=26774286; DOI=10.1016/j.molcel.2015.12.010; RA Zhang Q., Karnak D., Tan M., Lawrence T.S., Morgan M.A., Sun Y.; RT "FBXW7 facilitates nonhomologous end-joining via K63-linked RT polyubiquitylation of XRCC4."; RL Mol. Cell 61:419-433(2016). RN [55] RP FUNCTION, INTERACTION WITH NHEJ1, AND SUBCELLULAR LOCATION. RX PubMed=27437582; DOI=10.1038/nature18643; RA Brouwer I., Sitters G., Candelli A., Heerema S.J., Heller I., de Melo A.J., RA Zhang H., Normanno D., Modesti M., Peterman E.J., Wuite G.J.; RT "Sliding sleeves of XRCC4-XLF bridge DNA and connect fragments of broken RT DNA."; RL Nature 535:566-569(2016). RN [56] RP FUNCTION, PHOSPHORYLATION AT SER-193; SER-260; SER-304; SER-315; SER-320; RP THR-323; SER-327 AND SER-328, AND MUTAGENESIS OF SER-193; SER-260; SER-304; RP SER-315; SER-320; THR-323; SER-327 AND SER-328. RX PubMed=28500754; DOI=10.7554/elife.22900; RA Normanno D., Negrel A., de Melo A.J., Betzi S., Meek K., Modesti M.; RT "Mutational phospho-mimicry reveals a regulatory role for the XRCC4 and XLF RT C-terminal tails in modulating DNA bridging during classical non-homologous RT end joining."; RL Elife 6:0-0(2017). RN [57] RP FUNCTION, PHOSPHORYLATION AT SER-232 AND THR-233, AND INTERACTION WITH RP PNKP. RX PubMed=28453785; DOI=10.1093/nar/gkx275; RA Aceytuno R.D., Piett C.G., Havali-Shahriari Z., Edwards R.A., Rey M., RA Ye R., Javed F., Fang S., Mani R., Weinfeld M., Hammel M., Tainer J.A., RA Schriemer D.C., Lees-Miller S.P., Glover J.N.M.; RT "Structural and functional characterization of the PNKP-XRCC4-LigIV DNA RT repair complex."; RL Nucleic Acids Res. 45:6238-6251(2017). RN [58] RP PHOSPHORYLATION AT SER-260, AND MUTAGENESIS OF SER-260. RX PubMed=30247612; DOI=10.1093/jrr/rry072; RA Amiri Moghani A.R., Sharma M.K., Matsumoto Y.; RT "In cellulo phosphorylation of DNA double-strand break repair protein XRCC4 RT on Ser260 by DNA-PK."; RL J. Radiat. Res. 59:700-708(2018). RN [59] RP INTERACTION WITH POLL. RX PubMed=30250067; DOI=10.1038/s41467-018-06127-y; RA Craxton A., Munnur D., Jukes-Jones R., Skalka G., Langlais C., Cain K., RA Malewicz M.; RT "PAXX and its paralogs synergistically direct DNA polymerase lambda RT activity in DNA repair."; RL Nat. Commun. 9:3877-3877(2018). RN [60] RP FUNCTION, SUBCELLULAR LOCATION, PROTEOLYTIC CLEAVAGE, AND MUTAGENESIS OF RP 262-ASP--ASP-265; ILE-266; ARG-270; LYS-271; ARG-272; ARG-273 AND ARG-275. RX PubMed=33725486; DOI=10.1016/j.molcel.2021.02.025; RA Maruoka M., Zhang P., Mori H., Imanishi E., Packwood D.M., Harada H., RA Kosako H., Suzuki J.; RT "Caspase cleavage releases a nuclear protein fragment that stimulates RT phospholipid scrambling at the plasma membrane."; RL Mol. Cell 81:1397-1410(2021). RN [61] {ECO:0007744|PDB:1FU1} RP X-RAY CRYSTALLOGRAPHY (2.70 ANGSTROMS) OF 1-203, AND SUBUNIT. RX PubMed=11080143; DOI=10.1093/emboj/19.22.5962; RA Junop M.S., Modesti M., Guarne A., Ghirlando R., Gellert M., Yang W.; RT "Crystal structure of the Xrcc4 DNA repair protein and implications for end RT joining."; RL EMBO J. 19:5962-5970(2000). RN [62] RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 1-113 IN COMPLEX WITH LIG4. RX PubMed=11702069; DOI=10.1038/nsb725; RA Sibanda B.L., Critchlow S.E., Begun J., Pei X.Y., Jackson S.P., RA Blundell T.L., Pellegrini L.; RT "Crystal structure of an Xrcc4-DNA ligase IV complex."; RL Nat. Struct. Biol. 8:1015-1019(2001). RN [63] RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 1-203. RX PubMed=14607114; DOI=10.1016/j.jmb.2003.09.031; RA Modesti M., Junop M.S., Ghirlando R., van de Rakt M., Gellert M., Yang W., RA Kanaar R.; RT "Tetramerization and DNA ligase IV interaction of the DNA double-strand RT break repair protein XRCC4 are mutually exclusive."; RL J. Mol. Biol. 334:215-228(2003). RN [64] {ECO:0007744|PDB:3II6} RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) OF 1-203 IN COMPLEX WITH LIG4, AND RP INTERACTION WITH LIG4. RX PubMed=19332554; DOI=10.1128/mcb.01895-08; RA Wu P.Y., Frit P., Meesala S., Dauvillier S., Modesti M., Andres S.N., RA Huang Y., Sekiguchi J., Calsou P., Salles B., Junop M.S.; RT "Structural and functional interaction between the human DNA repair RT proteins DNA ligase IV and XRCC4."; RL Mol. Cell. Biol. 29:3163-3172(2009). RN [65] {ECO:0007744|PDB:3W03} RP X-RAY CRYSTALLOGRAPHY (8.49 ANGSTROMS) OF 1-164 IN COMPLEX WITH NHEJ1, AND RP INTERACTION WITH NHEJ1. RX PubMed=21936820; DOI=10.1042/bst0391387; RA Wu Q., Ochi T., Matak-Vinkovic D., Robinson C.V., Chirgadze D.Y., RA Blundell T.L.; RT "Non-homologous end-joining partners in a helical dance: structural studies RT of XLF-XRCC4 interactions."; RL Biochem. Soc. Trans. 39:1387-1392(2011). RN [66] {ECO:0007744|PDB:3SR2} RP X-RAY CRYSTALLOGRAPHY (3.97 ANGSTROMS) OF 1-140 IN COMPLEX WITH NHEJ1, RP FUNCTION, AND INTERACTION WITH NHEJ1. RX PubMed=21775435; DOI=10.1074/jbc.m111.272641; RA Hammel M., Rey M., Yu Y., Mani R.S., Classen S., Liu M., Pique M.E., RA Fang S., Mahaney B.L., Weinfeld M., Schriemer D.C., Lees-Miller S.P., RA Tainer J.A.; RT "XRCC4 protein interactions with XRCC4-like factor (XLF) create an extended RT grooved scaffold for DNA ligation and double strand break repair."; RL J. Biol. Chem. 286:32638-32650(2011). RN [67] {ECO:0007744|PDB:3RWR} RP X-RAY CRYSTALLOGRAPHY (3.94 ANGSTROMS) OF 1-157 IN COMPLEX WITH NHEJ1, RP FUNCTION, INTERACTION WITH NHEJ1, AND MUTAGENESIS OF LYS-65; LYS-72; RP LYS-90; LYS-99; GLU-170 AND ARG-192. RX PubMed=22287571; DOI=10.1093/nar/gks022; RA Andres S.N., Vergnes A., Ristic D., Wyman C., Modesti M., Junop M.; RT "A human XRCC4-XLF complex bridges DNA."; RL Nucleic Acids Res. 40:1868-1878(2012). RN [68] {ECO:0007744|PDB:3Q4F} RP X-RAY CRYSTALLOGRAPHY (5.50 ANGSTROMS) OF 1-157 IN COMPLEX WITH NHEJ1, RP FUNCTION, INTERACTION WITH NHEJ1, AND MUTAGENESIS OF GLU-55; ASP-58; RP MET-61; GLU-62; LYS-65; GLU-69 AND PHE-106. RX PubMed=21768349; DOI=10.1073/pnas.1100758108; RA Ropars V., Drevet P., Legrand P., Baconnais S., Amram J., Faure G., RA Marquez J.A., Pietrement O., Guerois R., Callebaut I., Le Cam E., Revy P., RA de Villartay J.P., Charbonnier J.B.; RT "Structural characterization of filaments formed by human Xrcc4- RT Cernunnos/XLF complex involved in nonhomologous DNA end-joining."; RL Proc. Natl. Acad. Sci. U.S.A. 108:12663-12668(2011). RN [69] {ECO:0007744|PDB:6ABO} RP X-RAY CRYSTALLOGRAPHY (2.65 ANGSTROMS) OF 1-213, SUBUNIT, INTERACTION WITH RP IFFO1, SUBCELLULAR LOCATION, AND REGION. RX PubMed=31548606; DOI=10.1038/s41556-019-0388-0; RA Li W., Bai X., Li J., Zhao Y., Liu J., Zhao H., Liu L., Ding M., Wang Q., RA Shi F.Y., Hou M., Ji J., Gao G., Guo R., Sun Y., Liu Y., Xu D.; RT "The nucleoskeleton protein IFFO1 immobilizes broken DNA and suppresses RT chromosome translocation during tumorigenesis."; RL Nat. Cell Biol. 21:1273-1285(2019). RN [70] {ECO:0007744|PDB:7NFC, ECO:0007744|PDB:7NFE} RP STRUCTURE BY ELECTRON MICROSCOPY (4.14 ANGSTROMS) IN COMPLEX WITH THE NHEJ RP COMPLEX AND DNA, AND IDENTIFICATION IN THE NHEJ COMPLEX. RX PubMed=34352203; DOI=10.1016/j.molcel.2021.07.005; RA Chaplin A.K., Hardwick S.W., Stavridi A.K., Buehl C.J., Goff N.J., RA Ropars V., Liang S., De Oliveira T.M., Chirgadze D.Y., Meek K., RA Charbonnier J.B., Blundell T.L.; RT "Cryo-EM of NHEJ supercomplexes provides insights into DNA repair."; RL Mol. Cell 81:3400-3409(2021). RN [71] {ECO:0007744|PDB:7LSY, ECO:0007744|PDB:7LT3} RP STRUCTURE BY ELECTRON MICROSCOPY (4.6 ANGSTROMS) IN COMPLEX WITH THE NHEJ RP COMPLEX, AND IDENTIFICATION IN THE NHEJ COMPLEX. RX PubMed=33854234; DOI=10.1038/s41586-021-03458-7; RA Chen S., Lee L., Naila T., Fishbain S., Wang A., Tomkinson A.E., RA Lees-Miller S.P., He Y.; RT "Structural basis of long-range to short-range synaptic transition in RT NHEJ."; RL Nature 593:294-298(2021). RN [72] RP VARIANTS SSMED ARG-43; 161-ARG--ILE-336 DEL; 225-ARG--ILE-336 DEL AND RP 275-ARG--ILE-336 DEL. RX PubMed=25728776; DOI=10.1016/j.ajhg.2015.01.013; RA Murray J.E., van der Burg M., Ijspeert H., Carroll P., Wu Q., Ochi T., RA Leitch A., Miller E.S., Kysela B., Jawad A., Bottani A., Brancati F., RA Cappa M., Cormier-Daire V., Deshpande C., Faqeih E.A., Graham G.E., RA Ranza E., Blundell T.L., Jackson A.P., Stewart G.S., Bicknell L.S.; RT "Mutations in the NHEJ component XRCC4 cause primordial dwarfism."; RL Am. J. Hum. Genet. 96:412-424(2015). RN [73] RP VARIANT SSMED 225-ARG--ILE-336 DEL. RX PubMed=25872942; DOI=10.15252/emmm.201404803; RA Bee L., Nasca A., Zanolini A., Cendron F., d'Adamo P., Costa R., RA Lamperti C., Celotti L., Ghezzi D., Zeviani M.; RT "A nonsense mutation of human XRCC4 is associated with adult-onset RT progressive encephalocardiomyopathy."; RL EMBO Mol. Med. 7:918-929(2015). RN [74] RP VARIANTS SSMED GLN-161 AND 275-ARG--ILE-336 DEL, AND CHARACTERIZATION OF RP VARIANT SSMED GLN-161. RX PubMed=25839420; DOI=10.1093/hmg/ddv115; RA Rosin N., Elcioglu N.H., Beleggia F., Isgueven P., Altmueller J., RA Thiele H., Steindl K., Joset P., Rauch A., Nuernberg P., Wollnik B., RA Yigit G.; RT "Mutations in XRCC4 cause primary microcephaly, short stature and increased RT genomic instability."; RL Hum. Mol. Genet. 24:3708-3717(2015). RN [75] RP VARIANTS SSMED ARG-43 AND 225-ARG--ILE-336 DEL, AND CHARACTERIZATION OF RP VARIANT SSMED ARG-43. RX PubMed=26255102; DOI=10.1016/j.jaci.2015.06.007; RA Guo C., Nakazawa Y., Woodbine L., Bjoerkman A., Shimada M., Fawcett H., RA Jia N., Ohyama K., Li T.S., Nagayama Y., Mitsutake N., Pan-Hammarstroem Q., RA Gennery A.R., Lehmann A.R., Jeggo P.A., Ogi T.; RT "XRCC4 deficiency in human subjects causes a marked neurological phenotype RT but no overt immunodeficiency."; RL J. Allergy Clin. Immunol. 136:1007-1017(2015). RN [76] RP VARIANT SSMED GLU-82, CHARACTERIZATION OF VARIANT SSMED GLU-82, AND RP FUNCTION. RX PubMed=25742519; DOI=10.1210/jc.2015-1098; RA de Bruin C., Mericq V., Andrew S.F., van Duyvenvoorde H.A., Verkaik N.S., RA Losekoot M., Porollo A., Garcia H., Kuang Y., Hanson D., Clayton P., RA van Gent D.C., Wit J.M., Hwa V., Dauber A.; RT "An XRCC4 splice mutation associated with severe short stature, gonadal RT failure, and early-onset metabolic syndrome."; RL J. Clin. Endocrinol. Metab. 100:E789-E798(2015). RN [77] RP VARIANT SSMED 210-LYS--ILE-336 DEL. RX PubMed=32524007; DOI=10.4158/accr-2019-0283; RA Fredette M.E., Lombardi K.C., Duker A.L., Buck C.O., Phornphutkul C., RA Bober M.B., Quintos J.B.; RT "Novel XRCC4 mutations in an infant with microcephalic primordial dwarfism, RT dilated cardiomyopathy, subclinical hypothyroidism, and early death: RT expanding the phenotype of XRCC4 mutations."; RL AACE Clin. Case Rep. 6:e1-e4(2020). CC -!- FUNCTION: [DNA repair protein XRCC4]: DNA non-homologous end joining CC (NHEJ) core factor, required for double-strand break repair and V(D)J CC recombination (PubMed:10757784, PubMed:10854421, PubMed:17124166, CC PubMed:16412978, PubMed:8548796, PubMed:25742519, PubMed:12517771, CC PubMed:17290226, PubMed:22228831, PubMed:25597996, PubMed:25934149, CC PubMed:26100018, PubMed:26774286). Acts as a scaffold protein that CC regulates recruitment of other proteins to DNA double-strand breaks CC (DSBs) (PubMed:15385968, PubMed:20852255, PubMed:26774286, CC PubMed:27437582). Associates with NHEJ1/XLF to form alternating helical CC filaments that bridge DNA and act like a bandage, holding together the CC broken DNA until it is repaired (PubMed:26100018, PubMed:27437582, CC PubMed:28500754, PubMed:21775435, PubMed:22287571, PubMed:21768349). CC The XRCC4-NHEJ1/XLF subcomplex binds to the DNA fragments of a DSB in a CC highly diffusive manner and robustly bridges two independent DNA CC molecules, holding the broken DNA fragments in close proximity to one CC other (PubMed:27437582). The mobility of the bridges ensures that the CC ends remain accessible for further processing by other repair factors CC (PubMed:27437582). Plays a key role in the NHEJ ligation step of the CC broken DNA during DSB repair via direct interaction with DNA ligase IV CC (LIG4): the LIG4-XRCC4 subcomplex reseals the DNA breaks after the gap CC filling is completed (PubMed:9242410, PubMed:10757784, PubMed:10854421, CC PubMed:12517771, PubMed:17290226, PubMed:19837014). XRCC4 stabilizes CC LIG4, regulates its subcellular localization and enhances LIG4's CC joining activity (PubMed:9242410, PubMed:10757784, PubMed:10854421, CC PubMed:12517771, PubMed:17290226, PubMed:21982441, PubMed:22228831). CC Binding of the LIG4-XRCC4 subcomplex to DNA ends is dependent on the CC assembly of the DNA-dependent protein kinase complex DNA-PK to these CC DNA ends (PubMed:10757784, PubMed:10854421). Promotes displacement of CC PNKP from processed strand break termini (PubMed:20852255, CC PubMed:28453785). {ECO:0000269|PubMed:10757784, CC ECO:0000269|PubMed:10854421, ECO:0000269|PubMed:12517771, CC ECO:0000269|PubMed:15385968, ECO:0000269|PubMed:16412978, CC ECO:0000269|PubMed:17124166, ECO:0000269|PubMed:17290226, CC ECO:0000269|PubMed:19837014, ECO:0000269|PubMed:20852255, CC ECO:0000269|PubMed:21768349, ECO:0000269|PubMed:21775435, CC ECO:0000269|PubMed:21982441, ECO:0000269|PubMed:22228831, CC ECO:0000269|PubMed:22287571, ECO:0000269|PubMed:25597996, CC ECO:0000269|PubMed:25742519, ECO:0000269|PubMed:25934149, CC ECO:0000269|PubMed:26100018, ECO:0000269|PubMed:26774286, CC ECO:0000269|PubMed:27437582, ECO:0000269|PubMed:28453785, CC ECO:0000269|PubMed:28500754, ECO:0000269|PubMed:8548796, CC ECO:0000269|PubMed:9242410}. CC -!- FUNCTION: [Protein XRCC4, C-terminus]: Acts as an activator of the CC phospholipid scramblase activity of XKR4 (PubMed:33725486). This form, CC which is generated upon caspase-3 (CASP3) cleavage, translocates into CC the cytoplasm and interacts with XKR4, thereby promoting CC phosphatidylserine scramblase activity of XKR4 and leading to CC phosphatidylserine exposure on apoptotic cell surface CC (PubMed:33725486). {ECO:0000269|PubMed:33725486}. CC -!- SUBUNIT: [DNA repair protein XRCC4]: Homodimer and homotetramer in CC solution (PubMed:25574025, PubMed:25670504, PubMed:25941166, CC PubMed:31548606, PubMed:11080143). Interacts with NHEJ1/XLF; the CC interaction is direct and is mediated via a head-to-head interaction CC between N-terminal head regions (PubMed:16439205, PubMed:18158905, CC PubMed:20558749, PubMed:22228831, PubMed:26100018, PubMed:27437582, CC PubMed:21936820, PubMed:21775435, PubMed:22287571, PubMed:21768349, CC PubMed:22658747). Interacts with LIG4; the LIG4-XRCC4 subcomplex has a CC 1:2 stoichiometry and XRCC4 is required for LIG4 stability CC (PubMed:9259561, PubMed:12517771, PubMed:17290226, PubMed:21982441, CC PubMed:24984242, PubMed:25934149, PubMed:11702069, PubMed:19332554, CC PubMed:9242410, PubMed:22658747). Component of the core long-range non- CC homologous end joining (NHEJ) complex (also named DNA-PK complex) CC composed of PRKDC, LIG4, XRCC4, XRCC6/Ku70, XRCC5/Ku86 and NHEJ1/XLF CC (PubMed:10757784, PubMed:10854421, PubMed:17124166, PubMed:12547193, CC PubMed:26774286, PubMed:33854234, PubMed:22658747, PubMed:34352203). CC Additional component of the NHEJ complex includes PAXX CC (PubMed:16439205). Following autophosphorylation, PRKDC dissociates CC from DNA, leading to formation of the short-range NHEJ complex, CC composed of LIG4, XRCC4, XRCC6/Ku70, XRCC5/Ku86 and NHEJ1/XLF CC (PubMed:33854234). Interacts with PRKDC; the interaction is direct CC (PubMed:12509254). Interacts with XRCC6/Ku70; the interaction is direct CC (PubMed:17124166). Interacts with APTX and APLF (PubMed:15380105, CC PubMed:17396150, PubMed:17353262, PubMed:18077224). Forms a CC heterotetramer with IFFO1; the interaction involves LIG4-free XRCC4 and CC leads to the relocalization of IFFO1 to the sites of DNA damage CC (PubMed:31548606). Interacts with PNKP; mainly interacts with PNKP when CC phosphorylated at Thr-233, but is also able to interact at much lower CC level with PNKP when not unphosphorylated (PubMed:15385968, CC PubMed:20852255, PubMed:28453785). Interacts with POLL (DNA polymerase CC lambda) (PubMed:30250067). {ECO:0000269|PubMed:10757784, CC ECO:0000269|PubMed:10854421, ECO:0000269|PubMed:11080143, CC ECO:0000269|PubMed:11702069, ECO:0000269|PubMed:12509254, CC ECO:0000269|PubMed:12517771, ECO:0000269|PubMed:12547193, CC ECO:0000269|PubMed:15380105, ECO:0000269|PubMed:15385968, CC ECO:0000269|PubMed:16439205, ECO:0000269|PubMed:17124166, CC ECO:0000269|PubMed:17290226, ECO:0000269|PubMed:17353262, CC ECO:0000269|PubMed:17396150, ECO:0000269|PubMed:18077224, CC ECO:0000269|PubMed:18158905, ECO:0000269|PubMed:19332554, CC ECO:0000269|PubMed:20558749, ECO:0000269|PubMed:20852255, CC ECO:0000269|PubMed:21768349, ECO:0000269|PubMed:21775435, CC ECO:0000269|PubMed:21936820, ECO:0000269|PubMed:21982441, CC ECO:0000269|PubMed:22228831, ECO:0000269|PubMed:22287571, CC ECO:0000269|PubMed:22658747, ECO:0000269|PubMed:24984242, CC ECO:0000269|PubMed:25574025, ECO:0000269|PubMed:25670504, CC ECO:0000269|PubMed:25934149, ECO:0000269|PubMed:25941166, CC ECO:0000269|PubMed:26100018, ECO:0000269|PubMed:26774286, CC ECO:0000269|PubMed:27437582, ECO:0000269|PubMed:28453785, CC ECO:0000269|PubMed:30250067, ECO:0000269|PubMed:31548606, CC ECO:0000269|PubMed:33854234, ECO:0000269|PubMed:34352203, CC ECO:0000269|PubMed:9242410, ECO:0000269|PubMed:9259561}. CC -!- SUBUNIT: [Protein XRCC4, C-terminus]: Interacts with XKR4; interacts CC with the processed form of XKR4, which is cleaved by caspase. CC {ECO:0000269|PubMed:33725486}. CC -!- INTERACTION: CC Q13426; Q8IW19: APLF; NbExp=5; IntAct=EBI-717592, EBI-1256044; CC Q13426; Q7Z2E3: APTX; NbExp=3; IntAct=EBI-717592, EBI-847814; CC Q13426; Q2TB18: ASTE1; NbExp=3; IntAct=EBI-717592, EBI-2875586; CC Q13426; O00499: BIN1; NbExp=4; IntAct=EBI-717592, EBI-719094; CC Q13426; Q8IZU0: FAM9B; NbExp=7; IntAct=EBI-717592, EBI-10175124; CC Q13426; O15499: GSC2; NbExp=3; IntAct=EBI-717592, EBI-19954058; CC Q13426; Q9NVX0: HAUS2; NbExp=3; IntAct=EBI-717592, EBI-720080; CC Q13426; Q0D2I5: IFFO1; NbExp=5; IntAct=EBI-717592, EBI-742894; CC Q13426; Q0D2I5-5: IFFO1; NbExp=4; IntAct=EBI-717592, EBI-21251044; CC Q13426; Q7Z3Y8: KRT27; NbExp=3; IntAct=EBI-717592, EBI-3044087; CC Q13426; P49917: LIG4; NbExp=19; IntAct=EBI-717592, EBI-847896; CC Q13426; P43360: MAGEA6; NbExp=3; IntAct=EBI-717592, EBI-1045155; CC Q13426; Q9H9Q4: NHEJ1; NbExp=11; IntAct=EBI-717592, EBI-847807; CC Q13426; Q9H9Q4-1: NHEJ1; NbExp=4; IntAct=EBI-717592, EBI-15891382; CC Q13426; Q96T60: PNKP; NbExp=9; IntAct=EBI-717592, EBI-1045072; CC Q13426; Q13426: XRCC4; NbExp=7; IntAct=EBI-717592, EBI-717592; CC Q13426; Q13426-3: XRCC4; NbExp=3; IntAct=EBI-717592, EBI-12699927; CC Q13426; P12956: XRCC6; NbExp=3; IntAct=EBI-717592, EBI-353208; CC Q13426-2; P49917: LIG4; NbExp=11; IntAct=EBI-15891375, EBI-847896; CC Q13426-2; Q9H9Q4-1: NHEJ1; NbExp=3; IntAct=EBI-15891375, EBI-15891382; CC Q13426-2; Q13426-2: XRCC4; NbExp=3; IntAct=EBI-15891375, EBI-15891375; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:16478998, CC ECO:0000269|PubMed:21982441, ECO:0000269|PubMed:24984242, CC ECO:0000269|PubMed:25597996, ECO:0000269|PubMed:25934149, CC ECO:0000269|PubMed:33725486, ECO:0000269|PubMed:9259561}. Chromosome CC {ECO:0000269|PubMed:26774286, ECO:0000269|PubMed:27437582, CC ECO:0000269|PubMed:31548606}. Note=Localizes to site of double-strand CC breaks. {ECO:0000269|PubMed:26774286, ECO:0000269|PubMed:27437582}. CC -!- SUBCELLULAR LOCATION: [Protein XRCC4, C-terminus]: Cytoplasm CC {ECO:0000269|PubMed:33725486}. Note=Translocates from the nucleus to CC the cytoplasm following cleavage by caspase-3 (CASP3). CC {ECO:0000269|PubMed:33725486}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=3; CC Name=1; CC IsoId=Q13426-1; Sequence=Displayed; CC Name=2; CC IsoId=Q13426-2; Sequence=VSP_009473; CC Name=3; CC IsoId=Q13426-3; Sequence=VSP_009474; CC -!- TISSUE SPECIFICITY: Widely expressed. {ECO:0000269|PubMed:8548796}. CC -!- PTM: Phosphorylated by PRKDC at the C-terminus in response to DNA CC damage; Ser-260 and Ser-320 constitute the main phosphorylation sites CC (PubMed:9430729, PubMed:15177042, PubMed:14599745, PubMed:12547193, CC PubMed:26666690, PubMed:28500754, PubMed:30247612). Phosphorylations by CC PRKDC at the C-terminus of XRCC4 and NHEJ1/XLF are highly redundant and CC regulate ability of the XRCC4-NHEJ1/XLF subcomplex to bridge DNA CC (PubMed:22228831, PubMed:28500754). Phosphorylation by PRKDC does not CC prevent interaction with NHEJ1/XLF but disrupts ability to bridge DNA CC and promotes detachment from DNA (PubMed:22228831, PubMed:28500754). CC Phosphorylation at Ser-327 and Ser-328 by PRKDC promotes recognition by CC the SCF(FBXW7) complex and subsequent ubiquitination via 'Lys-63'- CC linked ubiquitin (PubMed:26774286). Phosphorylation at Thr-233 by CK2 CC promotes interaction with PNKP; regulating PNKP activity and CC localization to DNA damage sites (PubMed:15385968, PubMed:20852255, CC PubMed:28453785). Phosphorylation by CK2 promotes interaction with APTX CC (PubMed:15380105). {ECO:0000269|PubMed:12547193, CC ECO:0000269|PubMed:14599745, ECO:0000269|PubMed:15177042, CC ECO:0000269|PubMed:15380105, ECO:0000269|PubMed:15385968, CC ECO:0000269|PubMed:20852255, ECO:0000269|PubMed:22228831, CC ECO:0000269|PubMed:26666690, ECO:0000269|PubMed:26774286, CC ECO:0000269|PubMed:28453785, ECO:0000269|PubMed:28500754, CC ECO:0000269|PubMed:30247612, ECO:0000269|PubMed:9430729}. CC -!- PTM: Ubiquitinated at Lys-296 by the SCF(FBXW7) complex via 'Lys-63'- CC linked ubiquitination, thereby promoting double-strand break repair: CC the SCF(FBXW7) complex specifically recognizes XRCC4 when CC phosphorylated at Ser-327 and Ser-328 by PRKDC, and 'Lys-63'-linked CC ubiquitination facilitates DNA non-homologous end joining (NHEJ) by CC enhancing association with XRCC5/Ku80 and XRCC6/Ku70 (PubMed:26774286). CC Monoubiquitinated (PubMed:16412978). {ECO:0000269|PubMed:16412978, CC ECO:0000269|PubMed:26774286}. CC -!- PTM: [DNA repair protein XRCC4]: Undergoes proteolytic processing by CC caspase-3 (CASP3) (Probable) (PubMed:33725486). This generates the CC protein XRCC4, C-terminus (XRCC4/C), which translocates to the CC cytoplasm and activates phospholipid scramblase activity of XKR4, CC thereby promoting phosphatidylserine exposure on apoptotic cell surface CC (PubMed:33725486). {ECO:0000269|PubMed:33725486, CC ECO:0000305|PubMed:10922471}. CC -!- DISEASE: Short stature, microcephaly, and endocrine dysfunction (SSMED) CC [MIM:616541]: A disease characterized by short stature and microcephaly CC apparent at birth, progressive postnatal growth failure, and endocrine CC dysfunction. In affected adults endocrine features include CC hypergonadotropic hypogonadism, multinodular goiter, and diabetes CC mellitus. Variable features observed in some patients are progressive CC ataxia, and lymphopenia or borderline leukopenia. CC {ECO:0000269|PubMed:24389050, ECO:0000269|PubMed:25728776, CC ECO:0000269|PubMed:25742519, ECO:0000269|PubMed:25839420, CC ECO:0000269|PubMed:25872942, ECO:0000269|PubMed:26255102, CC ECO:0000269|PubMed:32524007}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the XRCC4-XLF family. XRCC4 subfamily. CC {ECO:0000305}. CC -!- CAUTION: Sumoylation at Lys-210 was initially reported to regulate CC nuclear localization and recombination efficiency of XRCC4 CC (PubMed:16478998). This result is however not confirmed by another CC study (PubMed:25934149). {ECO:0000269|PubMed:16478998, CC ECO:0000269|PubMed:25934149}. CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/xrcc4/"; 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; U40622; AAC50339.1; -; mRNA. DR EMBL; AF055285; AAD47297.1; -; Genomic_DNA. DR EMBL; AF055279; AAD47297.1; JOINED; Genomic_DNA. DR EMBL; AF055280; AAD47297.1; JOINED; Genomic_DNA. DR EMBL; AF055281; AAD47297.1; JOINED; Genomic_DNA. DR EMBL; AF055282; AAD47297.1; JOINED; Genomic_DNA. DR EMBL; AF055283; AAD47297.1; JOINED; Genomic_DNA. DR EMBL; AF055284; AAD47297.1; JOINED; Genomic_DNA. DR EMBL; AF055285; AAD47298.1; -; Genomic_DNA. DR EMBL; AF055279; AAD47298.1; JOINED; Genomic_DNA. DR EMBL; AF055280; AAD47298.1; JOINED; Genomic_DNA. DR EMBL; AF055281; AAD47298.1; JOINED; Genomic_DNA. DR EMBL; AF055282; AAD47298.1; JOINED; Genomic_DNA. DR EMBL; AF055283; AAD47298.1; JOINED; Genomic_DNA. DR EMBL; AF055284; AAD47298.1; JOINED; Genomic_DNA. DR EMBL; AB017445; BAB20668.1; -; mRNA. DR EMBL; BT007216; AAP35880.1; -; mRNA. DR EMBL; AK290739; BAF83428.1; -; mRNA. DR EMBL; AY940097; AAX14046.1; -; Genomic_DNA. DR EMBL; CH471084; EAW95898.1; -; Genomic_DNA. DR EMBL; BC005259; AAH05259.1; -; mRNA. DR EMBL; BC016314; AAH16314.1; -; mRNA. DR CCDS; CCDS4058.1; -. [Q13426-2] DR CCDS; CCDS4059.1; -. [Q13426-1] DR RefSeq; NP_001304941.1; NM_001318012.1. [Q13426-1] DR RefSeq; NP_001304942.1; NM_001318013.1. [Q13426-3] DR RefSeq; NP_003392.1; NM_003401.4. [Q13426-2] DR RefSeq; NP_071801.1; NM_022406.3. [Q13426-1] DR RefSeq; NP_072044.1; NM_022550.3. [Q13426-2] DR RefSeq; XP_011541928.1; XM_011543626.1. [Q13426-1] DR PDB; 1FU1; X-ray; 2.70 A; A/B=1-203. DR PDB; 1IK9; X-ray; 2.30 A; A/B=1-213. DR PDB; 3II6; X-ray; 2.40 A; A/B/C/D=1-203. DR PDB; 3MUD; X-ray; 2.20 A; A/B=2-133. DR PDB; 3Q4F; X-ray; 5.50 A; C/D/G/H=1-157. DR PDB; 3RWR; X-ray; 3.94 A; A/B/F/G/J/K/N/P/R/U/V/Y=1-157. DR PDB; 3SR2; X-ray; 3.97 A; A/B/E/F=1-140. DR PDB; 3W03; X-ray; 8.49 A; C/D=1-164. DR PDB; 4XA4; X-ray; 2.33 A; A/B=2-147. DR PDB; 5CHX; X-ray; 2.30 A; A/B=2-143. DR PDB; 5CJ0; X-ray; 2.30 A; A/B=2-142. DR PDB; 5CJ4; X-ray; 3.10 A; A/B/C/D=2-144. DR PDB; 5E50; X-ray; 1.38 A; C/D=229-236. DR PDB; 5WJ7; X-ray; 2.50 A; A/B=2-132. DR PDB; 5WLZ; X-ray; 3.50 A; A/B/C/D=2-132. DR PDB; 6ABO; X-ray; 2.65 A; A=1-213. DR PDB; 7LSY; EM; 8.40 A; F/G/O/P=1-336. DR PDB; 7LT3; EM; 4.60 A; F/G/O/P=1-336. DR PDB; 7M3P; X-ray; 2.00 A; A/B=2-132. DR PDB; 7NFC; EM; 4.14 A; K/L/N/O=1-336. DR PDB; 7NFE; EM; 4.29 A; H/I=1-336. DR PDB; 8BH3; EM; 4.55 A; G/H/P/Q=1-336. DR PDB; 8BHV; EM; 4.51 A; K/L/N/O=1-336. DR PDB; 8BHY; EM; 5.33 A; G/H/P/Q=1-336. DR PDB; 8BOT; EM; 7.76 A; K/L/N/O=1-336. DR PDB; 8EZA; EM; 4.39 A; F/G/O/P=1-336. DR PDB; 8EZB; EM; 8.90 A; F/G/O/P=1-336. DR PDBsum; 1FU1; -. DR PDBsum; 1IK9; -. DR PDBsum; 3II6; -. DR PDBsum; 3MUD; -. DR PDBsum; 3Q4F; -. DR PDBsum; 3RWR; -. DR PDBsum; 3SR2; -. DR PDBsum; 3W03; -. DR PDBsum; 4XA4; -. DR PDBsum; 5CHX; -. DR PDBsum; 5CJ0; -. DR PDBsum; 5CJ4; -. DR PDBsum; 5E50; -. DR PDBsum; 5WJ7; -. DR PDBsum; 5WLZ; -. DR PDBsum; 6ABO; -. DR PDBsum; 7LSY; -. DR PDBsum; 7LT3; -. DR PDBsum; 7M3P; -. DR PDBsum; 7NFC; -. DR PDBsum; 7NFE; -. DR PDBsum; 8BH3; -. DR PDBsum; 8BHV; -. DR PDBsum; 8BHY; -. DR PDBsum; 8BOT; -. DR PDBsum; 8EZA; -. DR PDBsum; 8EZB; -. DR AlphaFoldDB; Q13426; -. DR EMDB; EMD-12299; -. DR EMDB; EMD-12301; -. DR EMDB; EMD-16044; -. DR EMDB; EMD-16070; -. DR EMDB; EMD-16074; -. DR EMDB; EMD-16145; -. DR EMDB; EMD-23509; -. DR EMDB; EMD-23510; -. DR EMDB; EMD-23512; -. DR EMDB; EMD-23515; -. DR EMDB; EMD-28732; -. DR EMDB; EMD-28733; -. DR EMDB; EMD-28736; -. DR EMDB; EMD-28739; -. DR SMR; Q13426; -. DR BioGRID; 113352; 114. DR ComplexPortal; CPX-618; DNA ligase IV complex. DR CORUM; Q13426; -. DR DIP; DIP-37957N; -. DR ELM; Q13426; -. DR IntAct; Q13426; 36. DR MINT; Q13426; -. DR STRING; 9606.ENSP00000421491; -. DR ChEMBL; CHEMBL4296097; -. DR DrugBank; DB03963; S-(Dimethylarsenic)Cysteine. DR iPTMnet; Q13426; -. DR MetOSite; Q13426; -. DR PhosphoSitePlus; Q13426; -. DR BioMuta; XRCC4; -. DR DMDM; 44888352; -. DR EPD; Q13426; -. DR jPOST; Q13426; -. DR MassIVE; Q13426; -. DR MaxQB; Q13426; -. DR PaxDb; 9606-ENSP00000421491; -. DR PeptideAtlas; Q13426; -. DR ProteomicsDB; 59412; -. [Q13426-1] DR ProteomicsDB; 59413; -. [Q13426-2] DR ProteomicsDB; 59414; -. [Q13426-3] DR Pumba; Q13426; -. DR Antibodypedia; 1873; 525 antibodies from 34 providers. DR DNASU; 7518; -. DR Ensembl; ENST00000282268.7; ENSP00000282268.3; ENSG00000152422.16. [Q13426-2] DR Ensembl; ENST00000338635.10; ENSP00000342011.6; ENSG00000152422.16. [Q13426-1] DR Ensembl; ENST00000396027.9; ENSP00000379344.4; ENSG00000152422.16. [Q13426-2] DR Ensembl; ENST00000511817.1; ENSP00000421491.1; ENSG00000152422.16. [Q13426-1] DR GeneID; 7518; -. DR KEGG; hsa:7518; -. DR MANE-Select; ENST00000396027.9; ENSP00000379344.4; NM_003401.5; NP_003392.1. [Q13426-2] DR UCSC; uc003kib.4; human. [Q13426-1] DR AGR; HGNC:12831; -. DR CTD; 7518; -. DR DisGeNET; 7518; -. DR GeneCards; XRCC4; -. DR HGNC; HGNC:12831; XRCC4. DR HPA; ENSG00000152422; Low tissue specificity. DR MalaCards; XRCC4; -. DR MIM; 194363; gene. DR MIM; 616541; phenotype. DR neXtProt; NX_Q13426; -. DR OpenTargets; ENSG00000152422; -. DR Orphanet; 99812; LIG4 syndrome. DR Orphanet; 436182; Microcephalic primordial dwarfism-insulin resistance syndrome. DR PharmGKB; PA37423; -. DR VEuPathDB; HostDB:ENSG00000152422; -. DR eggNOG; ENOG502QWJA; Eukaryota. DR GeneTree; ENSGT00390000017079; -. DR HOGENOM; CLU_072334_0_0_1; -. DR InParanoid; Q13426; -. DR OMA; MQKDISF; -. DR OrthoDB; 3672339at2759; -. DR PhylomeDB; Q13426; -. DR TreeFam; TF101204; -. DR PathwayCommons; Q13426; -. DR Reactome; R-HSA-164843; 2-LTR circle formation. DR Reactome; R-HSA-3108214; SUMOylation of DNA damage response and repair proteins. DR Reactome; R-HSA-5693571; Nonhomologous End-Joining (NHEJ). DR SignaLink; Q13426; -. DR SIGNOR; Q13426; -. DR BioGRID-ORCS; 7518; 87 hits in 1160 CRISPR screens. DR ChiTaRS; XRCC4; human. DR EvolutionaryTrace; Q13426; -. DR GeneWiki; XRCC4; -. DR GenomeRNAi; 7518; -. DR Pharos; Q13426; Tbio. DR PRO; PR:Q13426; -. DR Proteomes; UP000005640; Chromosome 5. DR RNAct; Q13426; Protein. DR Bgee; ENSG00000152422; Expressed in male germ line stem cell (sensu Vertebrata) in testis and 155 other cell types or tissues. DR ExpressionAtlas; Q13426; baseline and differential. DR GO; GO:0005829; C:cytosol; IDA:UniProtKB. DR GO; GO:0032807; C:DNA ligase IV complex; IDA:UniProtKB. DR GO; GO:0005958; C:DNA-dependent protein kinase-DNA ligase 4 complex; IDA:UniProtKB. DR GO; GO:0070419; C:nonhomologous end joining complex; IDA:UniProtKB. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0035861; C:site of double-strand break; IDA:UniProtKB. DR GO; GO:0070975; F:FHA domain binding; IPI:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0071285; P:cellular response to lithium ion; IEA:Ensembl. DR GO; GO:0051103; P:DNA ligation involved in DNA repair; IDA:UniProtKB. DR GO; GO:0006302; P:double-strand break repair; IDA:UniProtKB. DR GO; GO:0006303; P:double-strand break repair via nonhomologous end joining; IDA:UniProtKB. DR GO; GO:0033152; P:immunoglobulin V(D)J recombination; IBA:GO_Central. DR GO; GO:0051351; P:positive regulation of ligase activity; IDA:UniProtKB. DR GO; GO:1990166; P:protein localization to site of double-strand break; IDA:UniProtKB. DR GO; GO:0010165; P:response to X-ray; IDA:UniProtKB. DR CDD; cd22283; HD_XRCC4_N; 1. DR DisProt; DP00152; -. DR Gene3D; 1.20.5.370; -; 1. DR Gene3D; 2.170.210.10; DNA double-strand break repair and VJ recombination XRCC4, N-terminal; 1. DR InterPro; IPR010585; DNA_repair_prot_XRCC4. DR InterPro; IPR014751; XRCC4-like_C. DR InterPro; IPR038051; XRCC4-like_N_sf. DR InterPro; IPR009089; XRCC4_N_sf. DR PANTHER; PTHR28559; DNA REPAIR PROTEIN XRCC4; 1. DR PANTHER; PTHR28559:SF1; DNA REPAIR PROTEIN XRCC4; 1. DR Pfam; PF06632; XRCC4; 1. DR SUPFAM; SSF58022; XRCC4, C-terminal oligomerization domain; 1. DR SUPFAM; SSF50809; XRCC4, N-terminal domain; 1. DR Genevisible; Q13426; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Chromosome; Coiled coil; Cytoplasm; KW Disease variant; DNA damage; DNA recombination; DNA repair; DNA-binding; KW Dwarfism; Isopeptide bond; Nucleus; Phosphoprotein; Reference proteome; KW Ubl conjugation. FT CHAIN 1..336 FT /note="DNA repair protein XRCC4" FT /id="PRO_0000066047" FT CHAIN 266..336 FT /note="Protein XRCC4, C-terminus" FT /evidence="ECO:0000305|PubMed:33725486" FT /id="PRO_0000453296" FT REGION 1..213 FT /note="Interaction with IFFO1" FT /evidence="ECO:0000269|PubMed:31548606" FT REGION 180..213 FT /note="Interaction with LIG4" FT /evidence="ECO:0000269|PubMed:11702069" FT REGION 212..249 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 264..336 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COILED 131..165 FT /evidence="ECO:0000255" FT COILED 184..212 FT /evidence="ECO:0000255" FT MOTIF 270..275 FT /note="Nuclear localization signal" FT /evidence="ECO:0000269|PubMed:25934149, FT ECO:0000269|PubMed:33725486" FT COMPBIAS 295..318 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT SITE 265..266 FT /note="Cleavage; by caspase-3" FT /evidence="ECO:0000305|PubMed:33725486" FT MOD_RES 53 FT /note="Phosphoserine; by PRKDC" FT /evidence="ECO:0000269|PubMed:14599745" FT MOD_RES 193 FT /note="Phosphoserine; by PRKDC" FT /evidence="ECO:0000269|PubMed:14599745, FT ECO:0000269|PubMed:22228831, ECO:0000269|PubMed:28500754" FT MOD_RES 229 FT /note="Phosphotyrosine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 232 FT /note="Phosphoserine" FT /evidence="ECO:0000269|PubMed:28453785" FT MOD_RES 233 FT /note="Phosphothreonine; by CK2" FT /evidence="ECO:0000269|PubMed:15385968, FT ECO:0000269|PubMed:20852255, ECO:0000269|PubMed:28453785, FT ECO:0007744|PubMed:24275569" FT MOD_RES 237 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 256 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:20068231" FT MOD_RES 260 FT /note="Phosphoserine; by PRKDC" FT /evidence="ECO:0000269|PubMed:14599745, FT ECO:0000269|PubMed:15177042, ECO:0000269|PubMed:22228831, FT ECO:0000269|PubMed:28500754, ECO:0000269|PubMed:30247612, FT ECO:0007744|PubMed:23186163" FT MOD_RES 303 FT /note="Phosphoserine; by PRKDC" FT /evidence="ECO:0000269|PubMed:14599745, FT ECO:0000269|PubMed:22228831" FT MOD_RES 304 FT /note="Phosphoserine; by PRKDC" FT /evidence="ECO:0000269|PubMed:28500754, FT ECO:0007744|PubMed:23186163" FT MOD_RES 315 FT /note="Phosphoserine; by PRKDC" FT /evidence="ECO:0000269|PubMed:14599745, FT ECO:0000269|PubMed:22228831, ECO:0000269|PubMed:28500754" FT MOD_RES 320 FT /note="Phosphoserine; by PRKDC" FT /evidence="ECO:0000269|PubMed:14599745, FT ECO:0000269|PubMed:15177042, ECO:0000269|PubMed:22228831, FT ECO:0000269|PubMed:26666690, ECO:0000269|PubMed:28500754, FT ECO:0007744|PubMed:23186163" FT MOD_RES 323 FT /note="Phosphothreonine; by PRKDC" FT /evidence="ECO:0000269|PubMed:14599745, FT ECO:0000269|PubMed:22228831, ECO:0000269|PubMed:28500754" FT MOD_RES 327 FT /note="Phosphoserine; by PRKDC" FT /evidence="ECO:0000269|PubMed:14599745, FT ECO:0000269|PubMed:22228831, ECO:0000269|PubMed:26774286, FT ECO:0000269|PubMed:28500754, ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:19690332" FT MOD_RES 328 FT /note="Phosphoserine; by PRKDC" FT /evidence="ECO:0000269|PubMed:14599745, FT ECO:0000269|PubMed:22228831, ECO:0000269|PubMed:26774286, FT ECO:0000269|PubMed:28500754, ECO:0007744|PubMed:18669648, FT ECO:0007744|PubMed:19690332" FT CROSSLNK 210 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO)" FT /evidence="ECO:0000269|PubMed:16478998" FT CROSSLNK 296 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:26774286" FT VAR_SEQ 298..336 FT /note="NSRPDSSLPETSKKEHISAENMSLETLRNSSPEDLFDEI -> KGRKKETSE FT KEAV (in isoform 3)" FT /evidence="ECO:0000303|PubMed:15489334, ECO:0000303|Ref.4" FT /id="VSP_009474" FT VAR_SEQ 298..300 FT /note="NSR -> K (in isoform 2)" FT /evidence="ECO:0000303|PubMed:8548796" FT /id="VSP_009473" FT VARIANT 12 FT /note="S -> C (in dbSNP:rs28383138)" FT /evidence="ECO:0000269|Ref.6" FT /id="VAR_022310" FT VARIANT 43 FT /note="W -> R (in SSMED; impairs the protein function in FT DNA double-strand break repair; dbSNP:rs587779351)" FT /evidence="ECO:0000269|PubMed:24389050, FT ECO:0000269|PubMed:25728776, ECO:0000269|PubMed:26255102" FT /id="VAR_075822" FT VARIANT 56 FT /note="A -> T (in dbSNP:rs28383151)" FT /evidence="ECO:0000269|Ref.6" FT /id="VAR_022311" FT VARIANT 82 FT /note="D -> E (in SSMED; impaired ability to repair DNA FT double-strand breaks)" FT /evidence="ECO:0000269|PubMed:25742519" FT /id="VAR_084965" FT VARIANT 134 FT /note="I -> T (in dbSNP:rs28360135)" FT /evidence="ECO:0000269|Ref.6" FT /id="VAR_022312" FT VARIANT 142 FT /note="E -> Q (in dbSNP:rs28360136)" FT /evidence="ECO:0000269|Ref.6" FT /id="VAR_022313" FT VARIANT 161..336 FT /note="Missing (in SSMED)" FT /evidence="ECO:0000269|PubMed:25728776" FT /id="VAR_084966" FT VARIANT 161 FT /note="R -> Q (in SSMED; no expression of the protein is FT observed; complete loss of function in DNA double-strand FT break repair; dbSNP:rs797045017)" FT /evidence="ECO:0000269|PubMed:25839420" FT /id="VAR_075823" FT VARIANT 210..336 FT /note="Missing (in SSMED)" FT /evidence="ECO:0000269|PubMed:32524007" FT /id="VAR_084967" FT VARIANT 225..336 FT /note="Missing (in SSMED)" FT /evidence="ECO:0000269|PubMed:25728776, FT ECO:0000269|PubMed:25872942, ECO:0000269|PubMed:26255102" FT /id="VAR_084968" FT VARIANT 240 FT /note="Q -> P (in dbSNP:rs2974446)" FT /id="VAR_017810" FT VARIANT 247 FT /note="A -> S (in dbSNP:rs3734091)" FT /evidence="ECO:0000269|Ref.6" FT /id="VAR_017811" FT VARIANT 275..336 FT /note="Missing (in SSMED)" FT /evidence="ECO:0000269|PubMed:25728776, FT ECO:0000269|PubMed:25839420" FT /id="VAR_084969" FT MUTAGEN 4 FT /note="K->E: Abolished interaction with NHEJ1/XLF; when FT associated with E-99." FT /evidence="ECO:0000269|PubMed:18158905" FT MUTAGEN 26 FT /note="K->E: Abolished interaction with NHEJ1/XLF; when FT associated with E-99." FT /evidence="ECO:0000269|PubMed:18158905" FT MUTAGEN 55 FT /note="E->R: Abolished interaction with NHEJ1/XLF." FT /evidence="ECO:0000269|PubMed:21768349" FT MUTAGEN 58 FT /note="D->R: Abolished interaction with NHEJ1/XLF." FT /evidence="ECO:0000269|PubMed:21768349" FT MUTAGEN 61 FT /note="M->R: Abolished interaction with NHEJ1/XLF." FT /evidence="ECO:0000269|PubMed:21768349" FT MUTAGEN 62 FT /note="E->R: Does not affect interaction with NHEJ1/XLF." FT /evidence="ECO:0000269|PubMed:21768349" FT MUTAGEN 65 FT /note="K->E: Strongly decreased interaction with NHEJ1/XLF. FT Abolished interaction with NHEJ1/XLF; when associated with FT E-99. Abolished ability to bridge DNA; when associated with FT E-99. Abolished interaction with NHEJ1/XLF; when associated FT with E-102." FT /evidence="ECO:0000269|PubMed:18158905, FT ECO:0000269|PubMed:21768349, ECO:0000269|PubMed:22287571" FT MUTAGEN 69 FT /note="E->R: Does not affect interaction with NHEJ1/XLF." FT /evidence="ECO:0000269|PubMed:21768349" FT MUTAGEN 71 FT /note="R->E: Abolished interaction with NHEJ1/XLF; when FT associated with E-99." FT /evidence="ECO:0000269|PubMed:18158905" FT MUTAGEN 72 FT /note="K->E: Abolished interaction with NHEJ1/XLF; when FT associated with E-99. Abolished ability to bridge DNA; when FT associated with E-90 and E-99." FT /evidence="ECO:0000269|PubMed:18158905, FT ECO:0000269|PubMed:22287571" FT MUTAGEN 90 FT /note="K->E: Abolished ability to bridge DNA; when FT associated with E-72 and E-99." FT /evidence="ECO:0000269|PubMed:22287571" FT MUTAGEN 99 FT /note="K->E: Abolished interaction with NHEJ1/XLF; when FT associated with E-4 or E-26 or E-65 or E-71 or E-72. FT Abolished ability to bridge DNA; when associated with E-65. FT Abolished ability to bridge DNA; when associated with E-72 FT and E-90." FT /evidence="ECO:0000269|PubMed:18158905, FT ECO:0000269|PubMed:22287571" FT MUTAGEN 102 FT /note="K->E: Abolished interaction with NHEJ1/XLF; when FT associated with E-65." FT /evidence="ECO:0000269|PubMed:18158905" FT MUTAGEN 106 FT /note="F->E: Abolished interaction with NHEJ1/XLF." FT /evidence="ECO:0000269|PubMed:21768349" FT MUTAGEN 140 FT /note="K->R: No change in sumoylation." FT /evidence="ECO:0000269|PubMed:16478998" FT MUTAGEN 170 FT /note="E->A: Abolished DNA-binding." FT /evidence="ECO:0000269|PubMed:22287571" FT MUTAGEN 192 FT /note="R->A: Abolished DNA-binding." FT /evidence="ECO:0000269|PubMed:22287571" FT MUTAGEN 193 FT /note="S->A: In XRCC4-Ala mutant; abolished phosphorylation FT by PRKDC; does not affect ability to bridge DNA when FT associated with NHEJ1/XLF phosphorylation-defective mutant; FT when associated with A-260, A-304, A-315, A-320, A-323, FT A-327 and A-328." FT /evidence="ECO:0000269|PubMed:28500754" FT MUTAGEN 193 FT /note="S->D: In XRCC4-Asp mutant; phospho-mimetic mutant; FT abolished ability to bridge DNA when associated with FT NHEJ1/XLF phospho-mimetic mutant; when associated with FT D-260, D-304, D-315, D-320, D-323, D-327 and D-328." FT /evidence="ECO:0000269|PubMed:28500754" FT MUTAGEN 210 FT /note="K->R: Abolishes sumoylation. 5-fold decrease in FT recombination efficiency. Does not affect nuclear FT localization of XRCC4 and LIG4." FT /evidence="ECO:0000269|PubMed:16478998, FT ECO:0000269|PubMed:25934149" FT MUTAGEN 233 FT /note="T->A: Abolished phosphorylation by CK2, leading to FT strongly reduced interaction with PNKP." FT /evidence="ECO:0000269|PubMed:15385968" FT MUTAGEN 235 FT /note="E->F: Impaired ability mediate double-strand break FT repair." FT /evidence="ECO:0000269|PubMed:25597996" FT MUTAGEN 260 FT /note="S->A: Reduced phosphorylation by PRKDC. In XRCC4-Ala FT mutant; abolished phosphorylation by PRKDC; does not affect FT ability to bridge DNA when associated with NHEJ1/XLF FT phosphorylation-defective mutant; when associated with FT A-193, A-304, A-315, A-320, A-323, A-327 and A-328." FT /evidence="ECO:0000269|PubMed:14599745, FT ECO:0000269|PubMed:28500754, ECO:0000269|PubMed:30247612" FT MUTAGEN 260 FT /note="S->D: In XRCC4-Asp mutant; phospho-mimetic mutant; FT abolished ability to bridge DNA when associated with FT NHEJ1/XLF phospho-mimetic mutant; when associated with FT D-193, D-304, D-315, D-320, D-323, D-327 and D-328." FT /evidence="ECO:0000269|PubMed:28500754" FT MUTAGEN 262..265 FT /note="DVTD->AVTA: In 2DA; abolished cleavage by caspase FT and ability to regulate phospholipid scramblase activity." FT /evidence="ECO:0000269|PubMed:33725486" FT MUTAGEN 264 FT /note="T->A: Does not affect phosphorylation by CK2." FT /evidence="ECO:0000269|PubMed:15385968" FT MUTAGEN 266 FT /note="I->G: Abolished cleavage by caspase and ability to FT regulate phospholipid scramblase activity." FT /evidence="ECO:0000269|PubMed:33725486" FT MUTAGEN 270 FT /note="R->A: Impaired ability to localize in the nucleus." FT /evidence="ECO:0000269|PubMed:33725486" FT MUTAGEN 271 FT /note="K->A: Impaired ability to localize in the nucleus, FT without affecting ability to activate phospholipid FT scramblase activity of XKR4." FT /evidence="ECO:0000269|PubMed:33725486" FT MUTAGEN 271 FT /note="K->R: Abolished nuclear localization of XRCC4 and FT LIG4. Impaired ability to repair DNA double-strand breaks FT (DSBs). Reduced ubiquitination by the SCF(FBXW7) complex FT caused by impaired localization to the nucleus." FT /evidence="ECO:0000269|PubMed:25934149, FT ECO:0000269|PubMed:26774286" FT MUTAGEN 272 FT /note="R->A: Impaired ability to localize in the nucleus, FT without affecting ability to activate phospholipid FT scramblase activity of XKR4." FT /evidence="ECO:0000269|PubMed:33725486" FT MUTAGEN 273 FT /note="R->A: Impaired ability to localize in the nucleus, FT without affecting ability to activate phospholipid FT scramblase activity of XKR4." FT /evidence="ECO:0000269|PubMed:33725486" FT MUTAGEN 275 FT /note="R->A: Does not affect ability to localize into the FT nucleus." FT /evidence="ECO:0000269|PubMed:33725486" FT MUTAGEN 282 FT /note="T->A: Does not affect phosphorylation by CK2." FT /evidence="ECO:0000269|PubMed:15385968" FT MUTAGEN 285 FT /note="K->R: Does not affect ubiquitination by the FT SCF(FBXW7) complex." FT /evidence="ECO:0000269|PubMed:26774286" FT MUTAGEN 296 FT /note="K->R: Abolished ubiquitination by the SCF(FBXW7) FT complex." FT /evidence="ECO:0000269|PubMed:26774286" FT MUTAGEN 304 FT /note="S->A: In XRCC4-Ala mutant; abolished phosphorylation FT by PRKDC; does not affect ability to bridge DNA when FT associated with NHEJ1/XLF phosphorylation-defective mutant; FT when associated with A-193, A-260, A-315, A-320, A-323, FT A-327 and A-328." FT /evidence="ECO:0000269|PubMed:28500754" FT MUTAGEN 304 FT /note="S->D: In XRCC4-Asp mutant; phospho-mimetic mutant; FT abolished ability to bridge DNA when associated with FT NHEJ1/XLF phospho-mimetic mutant; when associated with FT D-193, D-260, D-315, D-320, D-323, D-327 and D-328." FT /evidence="ECO:0000269|PubMed:28500754" FT MUTAGEN 308 FT /note="T->A: Does not affect phosphorylation by CK2." FT /evidence="ECO:0000269|PubMed:15385968" FT MUTAGEN 308 FT /note="T->R: Does not affect ubiquitination by the FT SCF(FBXW7) complex." FT /evidence="ECO:0000269|PubMed:26774286" FT MUTAGEN 315 FT /note="S->A: In XRCC4-Ala mutant; abolished phosphorylation FT by PRKDC; does not affect ability to bridge DNA when FT associated with NHEJ1/XLF phosphorylation-defective mutant; FT when associated with A-193, A-260, A-304, A-320, A-323, FT A-327 and A-328." FT /evidence="ECO:0000269|PubMed:28500754" FT MUTAGEN 315 FT /note="S->D: In XRCC4-Asp mutant; phospho-mimetic mutant; FT abolished ability to bridge DNA when associated with FT NHEJ1/XLF phospho-mimetic mutant; when associated with FT D-193, D-260, D-304, D-320, D-323, D-327 and D-328." FT /evidence="ECO:0000269|PubMed:28500754" FT MUTAGEN 320 FT /note="S->A: Slightly reduced phosphorylation by PRKDC. In FT XRCC4-Ala mutant; abolished phosphorylation by PRKDC; does FT not affect ability to bridge DNA when associated with FT NHEJ1/XLF phosphorylation-defective mutant; when associated FT with A-193, A-260, A-304, A-315, A-323, A-327 and A-328." FT /evidence="ECO:0000269|PubMed:14599745, FT ECO:0000269|PubMed:28500754" FT MUTAGEN 320 FT /note="S->D: In XRCC4-Asp mutant; phospho-mimetic mutant; FT abolished ability to bridge DNA when associated with FT NHEJ1/XLF phospho-mimetic mutant; when associated with FT D-193, D-260, D-304, D-315, D-323, D-327 and D-328." FT /evidence="ECO:0000269|PubMed:28500754" FT MUTAGEN 322 FT /note="E->L: Does not affect ability mediate double-strand FT break repair." FT /evidence="ECO:0000269|PubMed:25597996" FT MUTAGEN 323 FT /note="T->A: In XRCC4-Ala mutant; abolished phosphorylation FT by PRKDC; does not affect ability to bridge DNA when FT associated with NHEJ1/XLF phosphorylation-defective mutant; FT when associated with A-193, A-260, A-304, A-315, A-320, FT A-327 and A-328. Does not affect phosphorylation by CK2." FT /evidence="ECO:0000269|PubMed:15385968, FT ECO:0000269|PubMed:28500754" FT MUTAGEN 323 FT /note="T->D: Does not affect ability mediate double-strand FT break repair. In XRCC4-Asp mutant; phospho-mimetic mutant; FT abolished ability to bridge DNA when associated with FT NHEJ1/XLF phospho-mimetic mutant; when associated with FT D-193, D-260, D-304, D-315, D-320, D-327 and D-328." FT /evidence="ECO:0000269|PubMed:25597996, FT ECO:0000269|PubMed:28500754" FT MUTAGEN 324 FT /note="L->W: Does not affect ability mediate double-strand FT break repair." FT /evidence="ECO:0000269|PubMed:25597996" FT MUTAGEN 326 FT /note="N->L: Abolished ability mediate double-strand break FT repair; impaired nuclear localization." FT /evidence="ECO:0000269|PubMed:25597996" FT MUTAGEN 327..328 FT /note="SS->AA: Reduced ubiquitination by the SCF(FBXW7) FT complex." FT /evidence="ECO:0000269|PubMed:26774286" FT MUTAGEN 327 FT /note="S->A: In XRCC4-Ala mutant; abolished phosphorylation FT by PRKDC; does not affect ability to bridge DNA when FT associated with NHEJ1/XLF phosphorylation-defective mutant; FT when associated with A-193, A-260, A-304, A-315, A-320, FT A-323 and A-328." FT /evidence="ECO:0000269|PubMed:28500754" FT MUTAGEN 327 FT /note="S->D: Does not affect ability mediate double-strand FT break repair. In XRCC4-Asp mutant; phospho-mimetic mutant; FT abolished ability to bridge DNA when associated with FT NHEJ1/XLF phospho-mimetic mutant; when associated with FT D-193, D-260, D-304, D-315, D-320, D-323 and D-328." FT /evidence="ECO:0000269|PubMed:25597996, FT ECO:0000269|PubMed:28500754" FT MUTAGEN 328 FT /note="S->A: In XRCC4-Ala mutant; abolished phosphorylation FT by PRKDC; does not affect ability to bridge DNA when FT associated with NHEJ1/XLF phosphorylation-defective mutant; FT when associated with A-193, A-260, A-304, A-315, A-320, FT A-323 and A-327." FT /evidence="ECO:0000269|PubMed:28500754" FT MUTAGEN 328 FT /note="S->D: Does not affect ability mediate double-strand FT break repair. In XRCC4-Asp mutant; phospho-mimetic mutant; FT abolished ability to bridge DNA when associated with FT NHEJ1/XLF phospho-mimetic mutant; when associated with FT D-193, D-260, D-304, D-315, D-320, D-323 and D-327." FT /evidence="ECO:0000269|PubMed:25597996, FT ECO:0000269|PubMed:28500754" FT MUTAGEN 329 FT /note="P->W: Does not affect ability mediate double-strand FT break repair." FT /evidence="ECO:0000269|PubMed:25597996" FT MUTAGEN 330 FT /note="E->L: Does not affect ability mediate double-strand FT break repair." FT /evidence="ECO:0000269|PubMed:25597996" FT MUTAGEN 331 FT /note="D->L: Does not affect ability mediate double-strand FT break repair." FT /evidence="ECO:0000269|PubMed:25597996" FT MUTAGEN 332 FT /note="L->W: Does not affect ability mediate double-strand FT break repair." FT /evidence="ECO:0000269|PubMed:25597996" FT MUTAGEN 333 FT /note="F->Y: Does not affect ability mediate double-strand FT break repair." FT /evidence="ECO:0000269|PubMed:25597996" FT MUTAGEN 334 FT /note="D->L: Does not affect ability mediate double-strand FT break repair." FT /evidence="ECO:0000269|PubMed:25597996" FT STRAND 2..10 FT /evidence="ECO:0007829|PDB:7M3P" FT STRAND 13..26 FT /evidence="ECO:0007829|PDB:7M3P" FT HELIX 28..30 FT /evidence="ECO:0007829|PDB:7M3P" FT STRAND 31..37 FT /evidence="ECO:0007829|PDB:7M3P" FT STRAND 42..48 FT /evidence="ECO:0007829|PDB:7M3P" FT HELIX 49..58 FT /evidence="ECO:0007829|PDB:7M3P" FT HELIX 63..74 FT /evidence="ECO:0007829|PDB:7M3P" FT TURN 79..81 FT /evidence="ECO:0007829|PDB:5WJ7" FT STRAND 84..89 FT /evidence="ECO:0007829|PDB:7M3P" FT TURN 90..93 FT /evidence="ECO:0007829|PDB:7M3P" FT STRAND 94..101 FT /evidence="ECO:0007829|PDB:7M3P" FT STRAND 104..112 FT /evidence="ECO:0007829|PDB:7M3P" FT HELIX 119..132 FT /evidence="ECO:0007829|PDB:7M3P" FT HELIX 142..145 FT /evidence="ECO:0007829|PDB:5CJ4" FT TURN 173..176 FT /evidence="ECO:0007829|PDB:1FU1" FT HELIX 179..201 FT /evidence="ECO:0007829|PDB:1FU1" SQ SEQUENCE 336 AA; 38287 MW; BE5FB99153479A4E CRC64; MERKISRIHL VSEPSITHFL QVSWEKTLES GFVITLTDGH SAWTGTVSES EISQEADDMA MEKGKYVGEL RKALLSGAGP ADVYTFNFSK ESCYFFFEKN LKDVSFRLGS FNLEKVENPA EVIRELICYC LDTIAENQAK NEHLQKENER LLRDWNDVQG RFEKCVSAKE ALETDLYKRF ILVLNEKKTK IRSLHNKLLN AAQEREKDIK QEGETAICSE MTADRDPVYD ESTDEESENQ TDLSGLASAA VSKDDSIISS LDVTDIAPSR KRRQRMQRNL GTEPKMAPQE NQLQEKENSR PDSSLPETSK KEHISAENMS LETLRNSSPE DLFDEI //