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

Oncogene volume 21, pages 4176–4180 (2002)Cite this article

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.

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References

  • Bishop DK, Ear U, Bhattacharyya A, Calderone C, Beckett M, Weichselbaum RR, Shinohara A . 1998 J. Biol. Chem. 273: 21482–21488

  • Brenneman MA, Weiss AE, Nickloff JA, Chen DJ . 2000 Mutat. Res. 459: 89–97

  • Butkiewicz D, Rusin M, Enewold L, Shields PG, Chorazy M, Harris CC . 2001 Carcinogenesis 22: 593–597

  • Cui X, Brenneman M, Meyne J, Oshimura M, Goodwin EH, Chen DJ . 1999 Mutat. Res. 434: 75–88

  • David-Beabes GL, Lunn RM, London SJ . 2001 Cancer Epidemiol. Biomarkers Prev. 10: 911–912

  • Griffin CS, Simpson PJ, Wilson CR, Thacker J . 2000 Nat. Cell Biol. 2: 757–761

  • Kurumizaka H, Ikawa S, Nakada M, Eda K, Kagawa W, Takata M, Takeda S, Yokoyama S, Shibata T . 2001 Proc. Natl. Acad. Sci. USA 98: 5538–5543

  • 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 . 1998 Mol. Cell 1: 783–793

  • Masson JY, Stasiak AZ, Stasiak A, Benson FE, West SC . 2001 Proc. Natl. Acad. Sci. USA 98: 8440–8446

  • Matullo G, Guarrera S, Carturan S, Peluso M, Malaveille C, Davico L, Piazza A, Vineis P . 2001 Int. J. Cancer 92: 562–567

  • Miyazaki J, Takaki S, Araki K, Tashiro F, Tominaga A, Takatsu K, Yamamura K . 1989 Gene 79: 269–277

  • Moynahan ME, Cui TY, Jasin M . 2001 Cancer Res. 61: 4842–4850

  • Pierce AJ, Hu P, Han M, Ellis N, Jasin M . 2001a Genes Dev. 15: 3237–3242

  • Pierce AJ, Johnson RD, Thompson LH, Jasin M . 1999 Genes Dev. 13: 2633–2638

  • Pierce AJ, Stark JM, Araujo FD, Moynahan ME, Berwick M, Jasin M . 2001b Trends Cell Biol. 11: S52–S59

  • Schild D, Lio Y, Collins DW, Tsomondo T, Chen DJ . 2000 J. Biol. Chem. 275: 16443–16449

  • Shen MR, Jones IM, Mohrenweiser H . 1998 Cancer Res. 58: 604–608

  • Tebbs RS, Zhao Y, Tucker JD, Scheerer JB, Siciliano MJ, Hwang M, Liu N, Legerski RJ, Thompson LH . 1995 Proc. Natl. Acad. Sci. USA 92: 6354–6358

  • Vogelstein B, Kinzler KW . 1998 The Genetic Basis of Human Cancer New York: McGraw-Hill

    Google Scholar 

  • Winsey SL, Haldar NA, Marsh HP, Bunce M, Marshall SE, Harris AL, Wojnarowska F, Welsh KI . 2000 Cancer Res. 60: 5612–5616

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Acknowledgements

We thank Marianne Berwick and Adam Olshen (MSKCC) for their assistance. This work was funded by NIH grant GM54688 to M Jasin.

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Authors and Affiliations

  1. Cell Biology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, 10021, NY, USA

    Felipe D Araujo, Andrew J Pierce, Jeremy M Stark & Maria Jasin

  2. Cornell University Weill Graduate School of Medical Sciences, 1275 York Avenue, New York, 10021, NY, USA

    Maria Jasin

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  1. Felipe D Araujo
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  2. Andrew J Pierce
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  3. Jeremy M Stark
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  4. Maria Jasin
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Correspondence to Maria Jasin.

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Araujo, F., Pierce, A., Stark, J. et al. Variant XRCC3 implicated in cancer is functional in homology-directed repair of double-strand breaks. Oncogene 21, 4176–4180 (2002). https://doi.org/10.1038/sj.onc.1205539

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