Variant XRCC3 implicated in cancer is functional in homology-directed repair of double-strand breaks Journal Article

Authors: Araujo, F. D.; Pierce, A. J.; Stark, J. M.; Jasin, M.
Article Title: Variant XRCC3 implicated in cancer is functional in homology-directed repair of double-strand breaks
Abstract: Polymorphisms in DNA repair genes, including double-strand break (DSB) repair genes, are postulated to confer increased cancer risk. A variant of the XRCC3 gene, which is involved in DSB repair, has been associated with increased risk of malignant skin melanoma and bladder cancer. We tested the hypothesis that this variant, Thr241Met, may affect cancer risk by disrupting a critical function of XRCC3, i.e., promoting homology-directed repair (HDR) of chromosomal DSBs. Using a quantitative fluorescence assay, we find that the variant XRCC3 protein is functionally active for HDR, complementing the HDR defects of an XRCC3 mutant cell line as well as the wild-type protein. We also examined cells expressing this variant for sensitivity to the interstrand cross-linking agent, mitomycin C (MMC), as HDR mutant cell lines, including the XRCC3 mutant, have been found to be hypersensitive to this DNA damaging agent. Cells expressing the variant protein were found to be no more sensitive than cells expressing the wild-type protein. These results suggest that the increased cancer risk associated with this variant may not be due to an intrinsic HDR defect.
Keywords: controlled study; unclassified drug; gene mutation; dna-binding proteins; cancer risk; nonhuman; animal cell; animals; homologous recombination; dna repair; gene expression; fluorescence; cell line; genetic variability; gene product; risk assessment; animalia; cancer genetics; amino acid sequence; molecular sequence data; recombination, genetic; mitomycin c; dna double-strand break repair; base sequence; genetic polymorphism; dna, complementary; polymorphism; genetic complementation; cricetinae; evolutionary homology; cross linking; rad51; protein xrcc3; xrcc3; priority journal; article
Journal Title: Oncogene
Volume: 21
Issue: 26
ISSN: 0950-9232
Publisher: Nature Publishing Group  
Date Published: 2002-06-13
Start Page: 4176
End Page: 4180
Language: English
DOI: 10.1038/sj.onc.1205539
PUBMED: 12037675
PROVIDER: scopus
Notes: Export Date: 14 November 2014 -- Source: Scopus
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MSK Authors
  1. Felipe Araujo
    2 Araujo
  2. Jeremy M Stark
    8 Stark
  3. Andrew J Pierce
    11 Pierce
  4. Maria Jasin
    210 Jasin