XRCC2

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External IDs	GeneCards: [1]
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Species	Human	Mouse
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DNA repair protein XRCC2 is a protein that in humans is encoded by the XRCC2 gene.

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 is involved in the repair of DNA double-strand breaks by homologous recombination and it functionally complements Chinese hamster irs1, a repair-deficient mutant that exhibits hypersensitivity to a number of different DNA-damaging agents.

The XRCC2 protein is one of five human 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.

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.

XRCC2 forms a four-part complex with three related paralogs: BCDX2 (RAD51B-RAD51C-RAD51D-XRCC2) while two paralogs form a second complex CX3 (RAD51C-XRCC3). These two complexes act at two different stages of homologous recombinational DNA repair. 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.

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

Interactions

XRCC2 has been shown to interact with RAD51L3, Bloom syndrome protein and RAD51C.

Epigenetic deficiency in cancer

There are two known epigenetic causes of XRCC2 deficiency that appear to increase cancer risk. These are methylation of the XRCC2 promoter and epigenetic repression of XRCC2 by over-expression of EZH2 protein.

The XRCC2 gene was found to be hypermethylated in the promoter region in 52 of 54 cases of cervical cancer. Promoter hypermethylation reduces gene expression, and thus would reduce the tumor suppressing homologous recombinational repair otherwise supported by XRCC2.

Increased expression of EZH2 leads to epigenetic repression of RAD51 paralogs, including XRCC2, and thus reduces homologous recombinational repair. 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. EZH2 protein is up-regulated in numerous cancers. EZH2 mRNA is up-regulated, on average, 7.5-fold in breast cancer, and between 40% to 75% of breast cancers have over-expressed EZH2 protein.

Further reading

• Thacker J, Tambini CE, Simpson PJ, Tsui LC, Scherer SW (Jan 1995). "Localization to chromosome 7q36.1 of the human XRCC2 gene, determining sensitivity to DNA-damaging agents". Human Molecular Genetics. 4 (1): 113–20. doi:10.1093/hmg/4.1.113. PMID 7711722.
• Tambini CE, George AM, Rommens JM, Tsui LC, Scherer SW, Thacker J (Apr 1997). "The XRCC2 DNA repair gene: identification of a positional candidate". Genomics. 41 (1): 84–92. doi:10.1006/geno.1997.4636. PMID 9126486.
• Cartwright R, Tambini CE, Simpson PJ, Thacker J (Jul 1998). "The XRCC2 DNA repair gene from human and mouse encodes a novel member of the recA/RAD51 family". Nucleic Acids Research. 26 (13): 3084–9. doi:10.1093/nar/26.13.3084. PMC 147676. PMID 9628903.
• 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 (May 1998). "XRCC2 and XRCC3, new human Rad51-family members, promote chromosome stability and protect against DNA cross-links and other damages". Molecular Cell. 1 (6): 783–93. doi:10.1016/S1097-2765(00)80078-7. PMID 9660962.
• Johnson RD, Liu N, Jasin M (Sep 1999). "Mammalian XRCC2 promotes the repair of DNA double-strand breaks by homologous recombination". Nature. 401 (6751): 397–9. doi:10.1038/43932. PMID 10517641.
• Schild D, Lio YC, Collins DW, Tsomondo T, Chen DJ (Jun 2000). "Evidence for simultaneous protein interactions between human Rad51 paralogs". The Journal of Biological Chemistry. 275 (22): 16443–9. doi:10.1074/jbc.M001473200. PMID 10749867.
• Braybrooke JP, Spink KG, Thacker J, Hickson ID (Sep 2000). "The RAD51 family member, RAD51L3, is a DNA-stimulated ATPase that forms a complex with XRCC2". The Journal of Biological Chemistry. 275 (37): 29100–6. doi:10.1074/jbc.M002075200. PMID 10871607.
• O'Regan P, Wilson C, Townsend S, Thacker J (Jun 2001). "XRCC2 is a nuclear RAD51-like protein required for damage-dependent RAD51 focus formation without the need for ATP binding". The Journal of Biological Chemistry. 276 (25): 22148–53. doi:10.1074/jbc.M102396200. PMID 11301337.
• Miller KA, Yoshikawa DM, McConnell IR, Clark R, Schild D, Albala JS (Mar 2002). "RAD51C interacts with RAD51B and is central to a larger protein complex in vivo exclusive of RAD51". The Journal of Biological Chemistry. 277 (10): 8406–11. doi:10.1074/jbc.M108306200. PMID 11744692.
• Masson JY, Tarsounas MC, Stasiak AZ, Stasiak A, Shah R, McIlwraith MJ, Benson FE, West SC (Dec 2001). "Identification and purification of two distinct complexes containing the five RAD51 paralogs". Genes & Development. 15 (24): 3296–307. doi:10.1101/gad.947001. PMC 312846. PMID 11751635.
• Kurumizaka H, Ikawa S, Nakada M, Enomoto R, Kagawa W, Kinebuchi T, Yamazoe M, Yokoyama S, Shibata T (Apr 2002). "Homologous pairing and ring and filament structure formation activities of the human Xrcc2*Rad51D complex". The Journal of Biological Chemistry. 277 (16): 14315–20. doi:10.1074/jbc.M105719200. PMID 11834724.
• Wiese C, Collins DW, Albala JS, Thompson LH, Kronenberg A, Schild D (Feb 2002). "Interactions involving the Rad51 paralogs Rad51C and XRCC3 in human cells". Nucleic Acids Research. 30 (4): 1001–8. doi:10.1093/nar/30.4.1001. PMC 100332. PMID 11842112.
• Liu N, Schild D, Thelen MP, Thompson LH (Feb 2002). "Involvement of Rad51C in two distinct protein complexes of Rad51 paralogs in human cells". Nucleic Acids Research. 30 (4): 1009–15. doi:10.1093/nar/30.4.1009. PMC 100342. PMID 11842113.
• Braybrooke JP, Li JL, Wu L, Caple F, Benson FE, Hickson ID (Nov 2003). "Functional interaction between the Bloom's syndrome helicase and the RAD51 paralog, RAD51L3 (RAD51D)". The Journal of Biological Chemistry. 278 (48): 48357–66. doi:10.1074/jbc.M308838200. PMID 12975363.
• Mohindra A, Bolderson E, Stone J, Wells M, Helleday T, Meuth M (Jan 2004). "A tumour-derived mutant allele of XRCC2 preferentially suppresses homologous recombination at DNA replication forks". Human Molecular Genetics. 13 (2): 203–12. doi:10.1093/hmg/ddh022. PMID 14645207.
• Tarsounas M, Davies AA, West SC (Jan 2004). "RAD51 localization and activation following DNA damage". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 359 (1441): 87–93. doi:10.1098/rstb.2003.1368. PMC 1693300. PMID 15065660.
• 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 (Jun 2004). "Direct interaction of FANCD2 with BRCA2 in DNA damage response pathways". Human Molecular Genetics. 13 (12): 1241–8. doi:10.1093/hmg/ddh135. PMID 15115758.