XRCC2

X-ray repair complementing defective repair in Chinese hamster cells 2
Identifiers
Symbols XRCC2 ; DKFZp781P0919
External IDs OMIM: 600375 MGI: 1927345 HomoloGene: 3964 GeneCards: XRCC2 Gene
RNA expression pattern
More reference expression data
Orthologs
Species Human Mouse
Entrez 7516 57434
Ensembl ENSG00000196584 ENSMUSG00000028933
UniProt O43543 Q9CX47
RefSeq (mRNA) NM_005431 NM_020570
RefSeq (protein) NP_005422 NP_065595
Location (UCSC) Chr 7:
152.64 – 152.68 Mb		 Chr 5:
25.69 – 25.71 Mb
PubMed search

DNA repair protein XRCC2 is a protein that in humans is encoded by the XRCC2 gene.[1][2][3]

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.[3]

The XRCC2 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.[4]

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.[5]

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.[5] 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.[5] The CX3 complex was shown to associate with Holliday junction resolvase activity, probably in a role of stabilizing gene conversion tracts.[5]

Interactions

XRCC2 has been shown to interact with RAD51L3,[6][7][8][9] Bloom syndrome protein[7] and RAD51C.[9][10]

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.[11] 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.[12] This reduction was proposed to be a cause of breast cancer.[12] 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.[13] EZH2 protein is up-regulated in numerous cancers.[13][14] 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.[15]

References

  1. ↑ Jones NJ, Zhao Y, Siciliano MJ, Thompson LH (Apr 1995). "Assignment of the XRCC2 human DNA repair gene to chromosome 7q36 by complementation analysis". Genomics 26 (3): 619–22. doi:10.1016/0888-7543(95)80187-Q. PMID 7607692.
  2. ↑ Cui X, Brenneman M, Meyne J, Oshimura M, Goodwin EH, Chen DJ (Jun 1999). "The XRCC2 and XRCC3 repair genes are required for chromosome stability in mammalian cells". Mutation Research 434 (2): 75–88. doi:10.1016/s0921-8777(99)00010-5. PMID 10422536.
  3. 1 2 "Entrez Gene: XRCC2 X-ray repair complementing defective repair in Chinese hamster cells 2".
  4. ↑ Miller KA, Sawicka D, Barsky D, Albala JS (2004). "Domain mapping of the Rad51 paralog protein complexes". Nucleic Acids Res. 32 (1): 169–78. doi:10.1093/nar/gkg925. PMC 373258. PMID 14704354.
  5. 1 2 3 4 Chun J, Buechelmaier ES, Powell SN (2013). "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. doi:10.1128/MCB.00465-12. PMC 3554112. PMID 23149936.
  6. ↑ 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.
  7. 1 2 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.
  8. ↑ 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.
  9. 1 2 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.
  10. ↑ 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.
  11. ↑ Paulíková S, Chmelařová M, Petera J, Palička V, Paulík A (2013). "Hypermethylation of RAD51L3 and XRCC2 genes to predict late toxicity in chemoradiotherapy-treated cervical cancer patients". Folia Biol. (Praha) 59 (6): 240–5. PMID 24485306.
  12. 1 2 Zeidler M, Kleer CG (2006). "The Polycomb group protein Enhancer of Zeste 2: its links to DNA repair and breast cancer". J. Mol. Histol. 37 (5-7): 219–23. doi:10.1007/s10735-006-9042-9. PMID 16855786.
  13. 1 2 Völkel P, Dupret B, Le Bourhis X, Angrand PO (2015). "Diverse involvement of EZH2 in cancer epigenetics". Am J Transl Res 7 (2): 175–93. PMC 4399085. PMID 25901190.
  14. ↑ Chang CJ, Hung MC (2012). "The role of EZH2 in tumour progression". Br. J. Cancer 106 (2): 243–7. doi:10.1038/bjc.2011.551. PMC 3261672. PMID 22187039.
  15. ↑ 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 (2003). "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. doi:10.1073/pnas.1933744100. PMC 208805. PMID 14500907.

Further reading

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