XRCC3_HUMAN
ID XRCC3_HUMAN Reviewed; 346 AA.
AC O43542; O43568; Q9BU18;
DT 03-APR-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1998, sequence version 1.
DT 03-AUG-2022, entry version 183.
DE RecName: Full=DNA repair protein XRCC3;
DE AltName: Full=X-ray repair cross-complementing protein 3;
GN Name=XRCC3;
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 [GENOMIC DNA / MRNA], AND VARIANT MET-241.
RC TISSUE=Cervix carcinoma;
RX PubMed=9660962; DOI=10.1016/s1097-2765(00)80078-7;
RA Liu N., Lamerdin J.E., Tebbs R.S., Schild D., Tucker J.D., Shen M.R.,
RA Brookman K.W., Siciliano M.J., Walter C.A., Fan W., Narayana L.S.,
RA Zhou Z.-Q., Adamson A.W., Sorensen K.J., Chen D.J., Jones N.J.,
RA Thompson L.H.;
RT "XRCC2 and XRCC3, new human Rad51-family members, promote chromosome
RT stability and protect against DNA cross-links and other damages.";
RL Mol. Cell 1:783-793(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS HIS-94 AND MET-241.
RG NIEHS SNPs program;
RL Submitted (APR-2002) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lymph, Muscle, and Placenta;
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 [4]
RP IDENTIFICATION IN THE CX3 COMPLEX WITH XRCC3.
RX PubMed=11751635; DOI=10.1101/gad.947001;
RA Masson J.Y., Tarsounas M.C., Stasiak A.Z., Stasiak A., Shah R.,
RA McIlwraith M.J., Benson F.E., West S.C.;
RT "Identification and purification of two distinct complexes containing the
RT five RAD51 paralogs.";
RL Genes Dev. 15:3296-3307(2001).
RN [5]
RP INVOLVEMENT IN BC SUSCEPTIBILITY.
RX PubMed=12023982; DOI=10.1093/hmg/11.12.1399;
RA Kuschel B., Auranen A., McBride S., Novik K.L., Antoniou A.,
RA Lipscombe J.M., Day N.E., Easton D.F., Ponder B.A., Pharoah P.D.,
RA Dunning A.;
RT "Variants in DNA double-strand break repair genes and breast cancer
RT susceptibility.";
RL Hum. Mol. Genet. 11:1399-1407(2002).
RN [6]
RP IDENTIFICATION IN THE CX3 COMPLEX WITH XRCC3.
RX PubMed=11744692; DOI=10.1074/jbc.m108306200;
RA Miller K.A., Yoshikawa D.M., McConnell I.R., Clark R., Schild D.,
RA Albala J.S.;
RT "RAD51C interacts with RAD51B and is central to a larger protein complex in
RT vivo exclusive of RAD51.";
RL J. Biol. Chem. 277:8406-8411(2002).
RN [7]
RP INTERACTION WITH RAD51 AND RAD51C.
RX PubMed=11842113; DOI=10.1093/nar/30.4.1009;
RA Liu N., Schild D., Thelen M.P., Thompson L.H.;
RT "Involvement of Rad51C in two distinct protein complexes of Rad51 paralogs
RT in human cells.";
RL Nucleic Acids Res. 30:1009-1015(2002).
RN [8]
RP INTERACTION WITH RAD51C.
RX PubMed=14704354; DOI=10.1093/nar/gkg925;
RA Miller K.A., Sawicka D., Barsky D., Albala J.S.;
RT "Domain mapping of the Rad51 paralog protein complexes.";
RL Nucleic Acids Res. 32:169-178(2004).
RN [9]
RP FUNCTION.
RX PubMed=14716019; DOI=10.1126/science.1093037;
RA Liu Y., Masson J.Y., Shah R., O'Regan P., West S.C.;
RT "RAD51C is required for Holliday junction processing in mammalian cells.";
RL Science 303:243-246(2004).
RN [10]
RP SUBCELLULAR LOCATION.
RX PubMed=16215984; DOI=10.1002/jcb.20640;
RA Bennett B.T., Knight K.L.;
RT "Cellular localization of human Rad51C and regulation of ubiquitin-mediated
RT proteolysis of Rad51.";
RL J. Cell. Biochem. 96:1095-1109(2005).
RN [11]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Embryonic kidney;
RX PubMed=17525332; DOI=10.1126/science.1140321;
RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, Hurov K.E.,
RA Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y.,
RA Gygi S.P., Elledge S.J.;
RT "ATM and ATR substrate analysis reveals extensive protein networks
RT responsive to DNA damage.";
RL Science 316:1160-1166(2007).
RN [12]
RP FUNCTION, SUBCELLULAR LOCATION, AND INDUCTION.
RX PubMed=20413593; DOI=10.1074/jbc.m109.099846;
RA Sage J.M., Gildemeister O.S., Knight K.L.;
RT "Discovery of a novel function for human Rad51: maintenance of the
RT mitochondrial genome.";
RL J. Biol. Chem. 285:18984-18990(2010).
RN [13]
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 [14]
RP INTERACTION WITH SWSAP1 AND ZSWIM7.
RX PubMed=21965664; DOI=10.1074/jbc.m111.271080;
RA Liu T., Wan L., Wu Y., Chen J., Huang J.;
RT "hSWS1.SWSAP1 is an evolutionarily conserved complex required for efficient
RT homologous recombination repair.";
RL J. Biol. Chem. 286:41758-41766(2011).
RN [15]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E.,
RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-terminal
RT acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [16]
RP FUNCTION IN HOLLIDAY JUNCTION RESOLUTION.
RX PubMed=23108668; DOI=10.1242/jcs.114595;
RA Rodrigue A., Coulombe Y., Jacquet K., Gagne J.P., Roques C., Gobeil S.,
RA Poirier G., Masson J.Y.;
RT "The RAD51 paralogs ensure cellular protection against mitotic defects and
RT aneuploidy.";
RL J. Cell Sci. 126:348-359(2013).
RN [17]
RP FUNCTION OF THE CX3 COMPLEX.
RX PubMed=23149936; DOI=10.1128/mcb.00465-12;
RA Chun J., Buechelmaier E.S., Powell S.N.;
RT "Rad51 paralog complexes BCDX2 and CX3 act at different stages in the
RT BRCA1-BRCA2-dependent homologous recombination pathway.";
RL Mol. Cell. Biol. 33:387-395(2013).
RN [18]
RP INTERACTION WITH PALB2, AND IDENTIFICATION IN A PALB2-CONTAINING HR
RP COMPLEX.
RX PubMed=24141787; DOI=10.1038/onc.2013.421;
RA Park J.Y., Singh T.R., Nassar N., Zhang F., Freund M., Hanenberg H.,
RA Meetei A.R., Andreassen P.R.;
RT "Breast cancer-associated missense mutants of the PALB2 WD40 domain, which
RT directly binds RAD51C, RAD51 and BRCA2, disrupt DNA repair.";
RL Oncogene 33:4803-4812(2014).
RN [19]
RP ELECTRON MICROSCOPY OF THE CX3 COMPLEX, AND DNA-BINDING OF THE CX3 COMPLEX.
RX PubMed=20207730; DOI=10.1074/jbc.m109.074286;
RA Compton S.A., Ozgur S., Griffith J.D.;
RT "Ring-shaped Rad51 paralog protein complexes bind Holliday junctions and
RT replication forks as visualized by electron microscopy.";
RL J. Biol. Chem. 285:13349-13356(2010).
RN [20]
RP VARIANT CMM6 MET-241.
RX PubMed=11059748;
RA Winsey S.L., Haldar N.A., Marsh H.P., Bunce M., Marshall S.E., Harris A.L.,
RA Wojnarowska F., Welsh K.I.;
RT "A variant within the DNA repair gene XRCC3 is associated with the
RT development of melanoma skin cancer.";
RL Cancer Res. 60:5612-5616(2000).
CC -!- FUNCTION: Involved in the homologous recombination repair (HRR) pathway
CC of double-stranded DNA, thought to repair chromosomal fragmentation,
CC translocations and deletions. Part of the RAD51 paralog protein complex
CC CX3 which acts in the BRCA1-BRCA2-dependent HR pathway. Upon DNA
CC damage, CX3 acts downstream of RAD51 recruitment; the complex binds
CC predominantly to the intersection of the four duplex arms of the
CC Holliday junction (HJ) and to junctions of replication forks. Involved
CC in HJ resolution and thus in processing HR intermediates late in the
CC DNA repair process; the function may be linked to the CX3 complex and
CC seems to involve GEN1 during mitotic cell cycle progression. Part of a
CC PALB2-scaffolded HR complex containing BRCA2 and RAD51C and which is
CC thought to play a role in DNA repair by HR. Plays a role in regulating
CC mitochondrial DNA copy number under conditions of oxidative stress in
CC the presence of RAD51 and RAD51C. {ECO:0000269|PubMed:14716019,
CC ECO:0000269|PubMed:20413593, ECO:0000269|PubMed:23108668,
CC ECO:0000269|PubMed:23149936}.
CC -!- SUBUNIT: Interacts with RAD51C and RAD51. Part of the CX3 complex
CC consisting of RAD51C and XRCC3; the complex has a ring-like structure
CC arranged into a flat disc around a central channel; CX3 can interact
CC with RAD51 in vitro. Forms a complex with FANCD2, BRCA2 and
CC phosphorylated FANCG. Interacts with SWSAP1 and ZSWIM7; involved in
CC homologous recombination repair. Interacts directly with PALB2 which
CC may serve as a scaffold for a HR complex containing PALB2, BRCA2,
CC RAD51C, RAD51 and XRCC3. {ECO:0000269|PubMed:11744692,
CC ECO:0000269|PubMed:11751635, ECO:0000269|PubMed:11842113,
CC ECO:0000269|PubMed:14704354, ECO:0000269|PubMed:21965664,
CC ECO:0000269|PubMed:24141787}.
CC -!- INTERACTION:
CC O43542; Q86YC2: PALB2; NbExp=3; IntAct=EBI-2849976, EBI-1222653;
CC O43542; Q06609: RAD51; NbExp=5; IntAct=EBI-2849976, EBI-297202;
CC O43542; O43502: RAD51C; NbExp=11; IntAct=EBI-2849976, EBI-2267048;
CC O43542; Q6NVH7: SWSAP1; NbExp=2; IntAct=EBI-2849976, EBI-5281637;
CC -!- SUBCELLULAR LOCATION: Nucleus. Cytoplasm. Cytoplasm, perinuclear
CC region. Mitochondrion. Note=Accumulates in discrete nuclear foci prior
CC to DNA damage, and these foci persist throughout the time course of DNA
CC repair.
CC -!- INDUCTION: Stress-induced increase in the mitochondrial levels is seen.
CC {ECO:0000269|PubMed:20413593}.
CC -!- DISEASE: Breast cancer (BC) [MIM:114480]: A common malignancy
CC originating from breast epithelial tissue. Breast neoplasms can be
CC distinguished by their histologic pattern. Invasive ductal carcinoma is
CC by far the most common type. Breast cancer is etiologically and
CC genetically heterogeneous. Important genetic factors have been
CC indicated by familial occurrence and bilateral involvement. Mutations
CC at more than one locus can be involved in different families or even in
CC the same case. {ECO:0000269|PubMed:12023982}. Note=Disease
CC susceptibility is associated with variants affecting the gene
CC represented in this entry.
CC -!- DISEASE: Melanoma, cutaneous malignant 6 (CMM6) [MIM:613972]: A
CC malignant neoplasm of melanocytes, arising de novo or from a pre-
CC existing benign nevus, which occurs most often in the skin but also may
CC involve other sites. {ECO:0000269|PubMed:11059748}. Note=Disease
CC susceptibility is associated with variants affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the RecA family. RAD51 subfamily. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/XRCC3ID335ch14q32.html";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/xrcc3/";
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; AF035586; AAC05368.1; -; mRNA.
DR EMBL; AF037222; AAC04805.1; -; Genomic_DNA.
DR EMBL; AF508041; AAM23015.1; -; Genomic_DNA.
DR EMBL; BC001036; AAH01036.1; -; mRNA.
DR EMBL; BC002949; AAH02949.1; -; mRNA.
DR EMBL; BC011725; AAH11725.1; -; mRNA.
DR CCDS; CCDS9984.1; -.
DR RefSeq; NP_001093588.1; NM_001100118.1.
DR RefSeq; NP_001093589.1; NM_001100119.1.
DR RefSeq; NP_005423.1; NM_005432.3.
DR RefSeq; XP_005268103.1; XM_005268046.2.
DR RefSeq; XP_011535440.1; XM_011537138.2.
DR AlphaFoldDB; O43542; -.
DR SMR; O43542; -.
DR BioGRID; 113351; 173.
DR CORUM; O43542; -.
DR DIP; DIP-42016N; -.
DR IntAct; O43542; 149.
DR MINT; O43542; -.
DR STRING; 9606.ENSP00000451974; -.
DR iPTMnet; O43542; -.
DR PhosphoSitePlus; O43542; -.
DR BioMuta; XRCC3; -.
DR EPD; O43542; -.
DR jPOST; O43542; -.
DR MassIVE; O43542; -.
DR PaxDb; O43542; -.
DR PeptideAtlas; O43542; -.
DR PRIDE; O43542; -.
DR ProteomicsDB; 49041; -.
DR Antibodypedia; 14778; 605 antibodies from 35 providers.
DR DNASU; 7517; -.
DR Ensembl; ENST00000352127.11; ENSP00000343392.7; ENSG00000126215.14.
DR Ensembl; ENST00000553264.5; ENSP00000451974.1; ENSG00000126215.14.
DR Ensembl; ENST00000554913.5; ENSP00000451362.1; ENSG00000126215.14.
DR Ensembl; ENST00000555055.6; ENSP00000452598.1; ENSG00000126215.14.
DR GeneID; 7517; -.
DR KEGG; hsa:7517; -.
DR MANE-Select; ENST00000555055.6; ENSP00000452598.1; NM_005432.4; NP_005423.1.
DR CTD; 7517; -.
DR DisGeNET; 7517; -.
DR GeneCards; XRCC3; -.
DR HGNC; HGNC:12830; XRCC3.
DR HPA; ENSG00000126215; Low tissue specificity.
DR MalaCards; XRCC3; -.
DR MIM; 114480; phenotype.
DR MIM; 600675; gene.
DR MIM; 613972; phenotype.
DR neXtProt; NX_O43542; -.
DR OpenTargets; ENSG00000126215; -.
DR PharmGKB; PA37422; -.
DR VEuPathDB; HostDB:ENSG00000126215; -.
DR eggNOG; KOG1564; Eukaryota.
DR GeneTree; ENSGT00930000151053; -.
DR HOGENOM; CLU_041732_1_0_1; -.
DR InParanoid; O43542; -.
DR OMA; PCLGLQW; -.
DR OrthoDB; 1341207at2759; -.
DR PhylomeDB; O43542; -.
DR TreeFam; TF101203; -.
DR PathwayCommons; O43542; -.
DR Reactome; R-HSA-5685942; HDR through Homologous Recombination (HRR).
DR Reactome; R-HSA-5693554; Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA).
DR Reactome; R-HSA-5693568; Resolution of D-loop Structures through Holliday Junction Intermediates.
DR Reactome; R-HSA-5693579; Homologous DNA Pairing and Strand Exchange.
DR SignaLink; O43542; -.
DR SIGNOR; O43542; -.
DR BioGRID-ORCS; 7517; 516 hits in 1084 CRISPR screens.
DR ChiTaRS; XRCC3; human.
DR GeneWiki; XRCC3; -.
DR GenomeRNAi; 7517; -.
DR Pharos; O43542; Tbio.
DR PRO; PR:O43542; -.
DR Proteomes; UP000005640; Chromosome 14.
DR RNAct; O43542; protein.
DR Bgee; ENSG00000126215; Expressed in mucosa of stomach and 95 other tissues.
DR ExpressionAtlas; O43542; baseline and differential.
DR Genevisible; O43542; HS.
DR GO; GO:0000781; C:chromosome, telomeric region; IC:BHF-UCL.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:UniProtKB.
DR GO; GO:0033065; C:Rad51C-XRCC3 complex; IDA:UniProtKB.
DR GO; GO:0005657; C:replication fork; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0140664; F:ATP-dependent DNA damage sensor activity; IEA:InterPro.
DR GO; GO:0003677; F:DNA binding; IEA:UniProtKB-KW.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; TAS:ProtInc.
DR GO; GO:0006310; P:DNA recombination; TAS:ProtInc.
DR GO; GO:0006281; P:DNA repair; IGI:BHF-UCL.
DR GO; GO:0000724; P:double-strand break repair via homologous recombination; IMP:UniProtKB.
DR GO; GO:0045003; P:double-strand break repair via synthesis-dependent strand annealing; IBA:GO_Central.
DR GO; GO:0036297; P:interstrand cross-link repair; IMP:ParkinsonsUK-UCL.
DR GO; GO:0090267; P:positive regulation of mitotic cell cycle spindle assembly checkpoint; IMP:UniProtKB.
DR GO; GO:0010824; P:regulation of centrosome duplication; IMP:UniProtKB.
DR GO; GO:0071140; P:resolution of mitotic recombination intermediates; IMP:UniProtKB.
DR GO; GO:0010033; P:response to organic substance; IEA:Ensembl.
DR GO; GO:0090656; P:t-circle formation; IMP:BHF-UCL.
DR GO; GO:0000722; P:telomere maintenance via recombination; IMP:BHF-UCL.
DR GO; GO:0090737; P:telomere maintenance via telomere trimming; IGI:BHF-UCL.
DR GO; GO:0090657; P:telomeric loop disassembly; TAS:BHF-UCL.
DR CDD; cd01123; Rad51_DMC1_radA; 1.
DR Gene3D; 3.40.50.300; -; 1.
DR InterPro; IPR013632; DNA_recomb/repair_Rad51_C.
DR InterPro; IPR016467; DNA_recomb/repair_RecA-like.
DR InterPro; IPR027417; P-loop_NTPase.
DR InterPro; IPR033925; Rad51_DMC1_RadA.
DR InterPro; IPR020588; RecA_ATP-bd.
DR Pfam; PF08423; Rad51; 1.
DR PIRSF; PIRSF005856; Rad51; 1.
DR SUPFAM; SSF52540; SSF52540; 1.
DR PROSITE; PS50162; RECA_2; 1.
PE 1: Evidence at protein level;
KW Acetylation; ATP-binding; Cytoplasm; Disease variant; DNA damage;
KW DNA recombination; DNA repair; DNA-binding; Mitochondrion;
KW Nucleotide-binding; Nucleus; Reference proteome.
FT CHAIN 1..346
FT /note="DNA repair protein XRCC3"
FT /id="PRO_0000122951"
FT BINDING 107..114
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0007744|PubMed:22814378"
FT VARIANT 94
FT /note="R -> H (in dbSNP:rs3212057)"
FT /evidence="ECO:0000269|Ref.2"
FT /id="VAR_020405"
FT VARIANT 241
FT /note="T -> M (in CMM6; risk factor for disease
FT development; dbSNP:rs861539)"
FT /evidence="ECO:0000269|PubMed:11059748,
FT ECO:0000269|PubMed:9660962, ECO:0000269|Ref.2"
FT /id="VAR_013006"
FT VARIANT 271
FT /note="G -> R (in dbSNP:rs28903080)"
FT /id="VAR_029295"
FT VARIANT 302
FT /note="R -> H (in dbSNP:rs28903081)"
FT /id="VAR_029296"
SQ SEQUENCE 346 AA; 37850 MW; 4DDF3B163C3B3332 CRC64;
MDLDLLDLNP RIIAAIKKAK LKSVKEVLHF SGPDLKRLTN LSSPEVWHLL RTASLHLRGS
SILTALQLHQ QKERFPTQHQ RLSLGCPVLD ALLRGGLPLD GITELAGRSS AGKTQLALQL
CLAVQFPRQH GGLEAGAVYI CTEDAFPHKR LQQLMAQQPR LRTDVPGELL QKLRFGSQIF
IEHVADVDTL LECVNKKVPV LLSRGMARLV VIDSVAAPFR CEFDSQASAP RARHLQSLGA
TLRELSSAFQ SPVLCINQVT EAMEEQGAAH GPLGFWDERV SPALGITWAN QLLVRLLADR
LREEEAALGC PARTLRVLSA PHLPPSSCSY TISAEGVRGT PGTQSH
