XRCC3 explained

DNA repair protein XRCC3 is a protein that in humans is encoded by the XRCC3 gene.^[1]

Function

This gene encodes a member of the RecA/Rad51-related protein family that participates in homologous recombination to maintain chromosome stability and repair DNA damage. This gene functionally complements Chinese hamster irs1SF, a repair-deficient mutant that exhibits hypersensitivity to a number of different DNA-damaging agents and is chromosomally unstable. A rare microsatellite polymorphism in this gene is associated with cancer in patients of varying radiosensitivity.^[2]

The XRCC3 protein is one of five paralogs of RAD51, including RAD51B (RAD51L1), RAD51C (RAD51L2), RAD51D (RAD51L3), XRCC2 and XRCC3. They each share about 25% amino acid sequence identity with RAD51 and each other.^[3]

The RAD51 paralogs are all required for efficient DNA double-strand break repair by homologous recombination and depletion of any paralog results in significant decreases in homologous recombination frequency.^[4]

Two paralogs form a complex designated CX3 (RAD51C-XRCC3). Four paralogs form a second complex designated BCDX2 (RAD51B-RAD51C-RAD51D-XRCC2). These two complexes act at two different stages of homologous recombinational DNA repair.

The CX3 complex acts downstream of RAD51, after its recruitment to damage sites. The CX3 complex associates with Holliday junction resolvase activity, probably in a role of stabilizing gene conversion tracts.

The BCDX2 complex is responsible for RAD51 recruitment or stabilization at damage sites. The BCDX2 complex appears to act by facilitating the assembly or stability of the RAD51 nucleoprotein filament.

Interactions

XRCC3 has been shown to interact with RAD51C.^{[5] [6] [7] [8]}

Epigenetic deficiency in cancer

There is an epigenetic cause of XRCC3 deficiency that appears to increase cancer risk. This is the repression of XRCC3 by over-expression of EZH2 protein.

Increased expression of EZH2 leads to epigenetic repression of RAD51 paralogs, including XRCC3, and thus reduces homologous recombinational repair.^[9] This reduction was proposed to be a cause of breast cancer. EZH2 is the catalytic subunit of Polycomb Repressor Complex 2 (PRC2) which catalyzes methylation of histone H3 at lysine 27 (H3K27me) and mediates gene silencing of target genes via local chromatin reorganization.^[10] EZH2 protein is up-regulated in numerous cancers.^[11] EZH2 mRNA is up-regulated, on average, 7.5-fold in breast cancer, and between 40% and 75% of breast cancers have over-expressed EZH2 protein.^[12]

See also

• XRCC2

Further reading

• Kopecný J . [Rational approaches to the treatment of urinary incontinence (author's transl)] . Ceskoslovenská Gynekologie . 41 . 6 . 408–9 . 1976 . 975276 .
• Price EA, Bourne SL, Radbourne R, Lawton PA, Lamerdin J, Thompson LH, Arrand JE . Rare microsatellite polymorphisms in the DNA repair genes XRCC1, XRCC3 and XRCC5 associated with cancer in patients of varying radiosensitivity . Somat. Cell Mol. Genet. . 23 . 4 . 237–247 . 1998 . 9542526 . 10.1007/BF02674415 . 32956047 .
• Liu N, Lamerdin JE, Tebbs RS, Schild D, Tucker JD, Shen MR, Brookman KW, Siciliano MJ, Walter CA, Fan W, Narayana LS, Zhou ZQ, Adamson AW, Sorensen KJ, Chen DJ, Jones NJ, Thompson LH . XRCC2 and XRCC3, new human Rad51-family members, promote chromosome stability and protect against DNA cross-links and other damages . Mol. Cell . 1 . 6 . 783–793 . 1998 . 9660962 . 10.1016/S1097-2765(00)80078-7 . free .
• Pierce AJ, Johnson RD, Thompson LH, Jasin M . XRCC3 promotes homology-directed repair of DNA damage in mammalian cells . Genes Dev. . 13 . 20 . 2633–2638 . 1999 . 10541549 . 317094 . 10.1101/gad.13.20.2633 .
• Winsey SL, Haldar NA, Marsh HP, Bunce M, Marshall SE, Harris AL, Wojnarowska F, Welsh KI . A variant within the DNA repair gene XRCC3 is associated with the development of melanoma skin cancer . Cancer Res. . 60 . 20 . 5612–6 . 2000 . 11059748 .
• Kurumizaka H, Ikawa S, Nakada M, Eda K, Kagawa W, Takata M, Takeda S, Yokoyama S, Shibata T . Homologous-pairing activity of the human DNA-repair proteins Xrcc3.Rad51C . Proc. Natl. Acad. Sci. U.S.A. . 98 . 10 . 5538–5543 . 2001 . 11331762 . 33248 . 10.1073/pnas.091603098 . free .
• Masson JY, Stasiak AZ, Stasiak A, Benson FE, West SC . Complex formation by the human RAD51C and XRCC3 recombination repair proteins . Proc. Natl. Acad. Sci. U.S.A. . 98 . 15 . 8440–8446 . 2001 . 11459987 . 37455 . 10.1073/pnas.111005698 . 2001PNAS...98.8440M . free .
• Miller KA, Yoshikawa DM, McConnell IR, Clark R, Schild D, Albala JS . RAD51C interacts with RAD51B and is central to a larger protein complex in vivo exclusive of RAD51 . J. Biol. Chem. . 277 . 10 . 8406–8411 . 2002 . 11744692 . 10.1074/jbc.M108306200 . free .
• Liu N, Schild D, Thelen MP, Thompson LH . Involvement of Rad51C in two distinct protein complexes of Rad51 paralogs in human cells . Nucleic Acids Res. . 30 . 4 . 1009–1015 . 2002 . 11842113 . 100342 . 10.1093/nar/30.4.1009 .
• Shen H, Sturgis EM, Dahlstrom KR, Zheng Y, Spitz MR, Wei Q . A variant of the DNA repair gene XRCC3 and risk of squamous cell carcinoma of the head and neck: a case-control analysis . Int. J. Cancer . 99 . 6 . 869–872 . 2002 . 12115490 . 10.1002/ijc.10413 . free .
• Duan Z, Shen H, Lee JE, Gershenwald JE, Ross MI, Mansfield PF, Duvic M, Strom SS, Spitz MR, Wei Q . DNA repair gene XRCC3 241Met variant is not associated with risk of cutaneous malignant melanoma . Cancer Epidemiol. Biomarkers Prev. . 11 . 10 Pt 1 . 1142–3 . 2002 . 12376526 .
• Seedhouse C, Bainton R, Lewis M, Harding A, Russell N, Das-Gupta E . The genotype distribution of the XRCC1 gene indicates a role for base excision repair in the development of therapy-related acute myeloblastic leukemia . Blood . 100 . 10 . 3761–3766 . 2003 . 12393447 . 10.1182/blood-2002-04-1152 . free .
• Smith TR, Miller MS, Lohman K, Lange EM, Case LD, Mohrenweiser HW, Hu JJ . Polymorphisms of XRCC1 and XRCC3 genes and susceptibility to breast cancer . Cancer Lett. . 190 . 2 . 183–190 . 2003 . 12565173 . 10.1016/S0304-3835(02)00595-5 .
• Jacobsen NR, Nexø BA, Olsen A, Overvad K, Wallin H, Tjønneland A, Vogel U . No association between the DNA repair gene XRCC3 T241M polymorphism and risk of skin cancer and breast cancer . Cancer Epidemiol. Biomarkers Prev. . 12 . 6 . 584–5 . 2004 . 12815008 .
• Zhu G, Duffy DL, Turner DR, Ewen KR, Montgomery GW, Martin NG . Linkage and association analysis of radiation damage repair genes XRCC3 and XRCC5 with nevus density in adolescent twins . Twin Research . 6 . 4 . 315–321 . 2005 . 14511439 . 10.1375/136905203322296683 . 2328/10191 . free.
• Bertram CG, Gaut RM, Barrett JH, Randerson-Moor J, Whitaker L, Turner F, Bataille V, dos Santos Silva I, Swerdlow AJ, Bishop DT, Newton Bishop JA . An assessment of a variant of the DNA repair gene XRCC3 as a possible nevus or melanoma susceptibility genotype . J. Invest. Dermatol. . 122 . 2 . 429–432 . 2004 . 15009726 . 10.1046/j.0022-202X.2003.12541.x . free .
• Tarsounas M, Davies AA, West SC . RAD51 localization and activation following DNA damage . Philos. Trans. R. Soc. Lond. B Biol. Sci. . 359 . 1441 . 87–93 . 2004 . 15065660 . 1693300 . 10.1098/rstb.2003.1368 .

Notes and References

1. Tebbs RS, Zhao Y, Tucker JD, Scheerer JB, Siciliano MJ, Hwang M, Liu N, Legerski RJ, Thompson LH . Correction of chromosomal instability and sensitivity to diverse mutagens by a cloned cDNA of the XRCC3 DNA repair gene . Proc Natl Acad Sci U S A . 92 . 14 . 6354–6358 . August 1995 . 7603995 . 41516 . 10.1073/pnas.92.14.6354 . 1995PNAS...92.6354T . free .
2. Web site: Entrez Gene: XRCC3 X-ray repair complementing defective repair in Chinese hamster cells 3.
3. Miller KA, Sawicka D, Barsky D, Albala JS . Domain mapping of the Rad51 paralog protein complexes . Nucleic Acids Res. . 32 . 1 . 169–78 . 2004 . 14704354 . 373258 . 10.1093/nar/gkg925 .
4. Chun J, Buechelmaier ES, Powell SN . Rad51 paralog complexes BCDX2 and CX3 act at different stages in the BRCA1-BRCA2-dependent homologous recombination pathway . Mol. Cell. Biol. . 33 . 2 . 387–95 . 2013 . 23149936 . 3554112 . 10.1128/MCB.00465-12 .
5. Hussain S, Wilson JB, Medhurst AL, Hejna J, Witt E, Ananth S, Davies A, Masson JY, Moses R, West SC, de Winter JP, Ashworth A, Jones NJ, Mathew CG . Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways . Hum. Mol. Genet. . 13 . 12 . 1241–8 . June 2004 . 15115758 . 10.1093/hmg/ddh135 . free .
6. Miller KA, Yoshikawa DM, McConnell IR, Clark R, Schild D, Albala JS . RAD51C interacts with RAD51B and is central to a larger protein complex in vivo exclusive of RAD51 . J. Biol. Chem. . 277 . 10 . 8406–11 . March 2002 . 11744692 . 10.1074/jbc.M108306200 . free .
7. Liu N, Schild D, Thelen MP, Thompson LH . Involvement of Rad51C in two distinct protein complexes of Rad51 paralogs in human cells . Nucleic Acids Res. . 30 . 4 . 1009–15 . February 2002 . 11842113 . 100342 . 10.1093/nar/30.4.1009.
8. Kurumizaka H, Ikawa S, Nakada M, Eda K, Kagawa W, Takata M, Takeda S, Yokoyama S, Shibata T . Homologous-pairing activity of the human DNA-repair proteins Xrcc3.Rad51C . Proc. Natl. Acad. Sci. U.S.A. . 98 . 10 . 5538–43 . May 2001 . 11331762 . 33248 . 10.1073/pnas.091603098 . free .
9. Zeidler M, Kleer CG . The Polycomb group protein Enhancer of Zeste 2: its links to DNA repair and breast cancer . J. Mol. Histol. . 37 . 5–7 . 219–23 . 2006 . 16855786 . 10.1007/s10735-006-9042-9 . 2332105 .
10. Völkel P, Dupret B, Le Bourhis X, Angrand PO . Diverse involvement of EZH2 in cancer epigenetics . Am J Transl Res . 7 . 2 . 175–93 . 2015 . 25901190 . 4399085 .
11. Chang CJ, Hung MC . The role of EZH2 in tumour progression . Br. J. Cancer . 106 . 2 . 243–7 . 2012 . 22187039 . 3261672 . 10.1038/bjc.2011.551 .
12. Kleer CG, Cao Q, Varambally S, Shen R, Ota I, Tomlins SA, Ghosh D, Sewalt RG, Otte AP, Hayes DF, Sabel MS, Livant D, Weiss SJ, Rubin MA, Chinnaiyan AM . EZH2 is a marker of aggressive breast cancer and promotes neoplastic transformation of breast epithelial cells . Proc. Natl. Acad. Sci. U.S.A. . 100 . 20 . 11606–11 . 2003 . 14500907 . 208805 . 10.1073/pnas.1933744100 . 2003PNAS..10011606K . free .