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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on April 20, 2005; DOI: 10.1124/jpet.105.084053

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Received for publication January 27, 2005.
Revised April 15, 2005.
Accepted for publication April 18, 2005.

XRCC3 induces cisplatin resistance by stimulation of Rad51-related recombinational repair, S-phase check point activation, and reduced apoptosis

Zhiyuan Xu 1, Martin Loignon 2, Feiyu Han 3, Lawrence C. Panasci 2*, Raquel Aloyz 4

1 Lady Davis Institute for Medical Research, Sir Mortimer B. Davis - Jewish General Hospital 2 Lady Davis Institute-Jewish General Hospital 3 Pathology and Human Genetics, McGill University and Cytogenetics, McGill University Hospital Center 4 Jewish General Hospital

* Address correspondence to: E-mail: lpanasci{at}hotmail.com

Abstract

Eukaryotic cells respond to DNA damage by activation of DNA repair, cell-cycle arrest and apoptosis. Several reports suggest that such responses may be coordinated by communication between damage repair proteins and proteins signalling other cellular responses. The Rad51-guided homologous recombination repair system plays an important role in recognition and repair of DNA interstrand crosslinks (ICLs) and cells deficient in this repair pathway become hypersensitive to ICL inducing- agents such as cisplatin and melphalan. We investigated the possible role of the Rad51-paralog protein, Xrcc3, in drug resistance. Xrcc3 overexpression in MCF-7 cell resulted in: (a) a 2-6 fold resistance to cisplatin/melphalan, (b) a 2 fold increase in drug-induced Rad51 foci, (c) an increased cisplatin-induced S-phase arrest (d) decreased cisplatin-induced apoptosis and (e) increased cisplatin-induced DNA synthesis arrest. Interestingly, Xrcc3 overexpression did not alter the doubling time or cell cycle progression in the absence of DNA damage. Furthermore, Xrcc3 overexpression is associated with increased Rad51C protein levels consistent with the known interaction of these two proteins. Our results demonstrate that Xrcc3 is an important factor in DNA cross-linking drug resistance in human tumor cells and suggest that the response of the homologous recombinational repair machinery and cell cycle checkpoints to DNA crosslinking agents is intertwined.


Key words: DNA repair, Rad51, Xrcc3, cell cycle, cisplatin, resistance


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