PT  - JOURNAL ARTICLE
AU  - Zhi-Yuan Xu
AU  - Martin Loignon
AU  - Fei-Yu Han
AU  - Lawrence Panasci
AU  - Raquel Aloyz
TI  - Xrcc3 Induces Cisplatin Resistance by Stimulation of Rad51-Related Recombinational Repair, S-Phase Checkpoint Activation, and Reduced Apoptosis
AID  - 10.1124/jpet.105.084053
DP  - 2005 Aug 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 495--505
VI  - 314
IP  - 2
4099  - http://jpet.aspetjournals.org/content/314/2/495.short
4100  - http://jpet.aspetjournals.org/content/314/2/495.full
SO  - J Pharmacol Exp Ther2005 Aug 01; 314
AB  - 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 signaling other cellular responses. The Rad51-guided homologous recombination repair system plays an important role in the 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 cells resulted in 1) a 2- to 6-fold resistance to cisplatin/melphalan, 2) a 2-fold increase in drug-induced Rad51 foci, 3) an increased cisplatin-induced S-phase arrest, 4) decreased cisplatin-induced apoptosis, and 5) 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 cross-linking agents is intertwined. The American Society for Pharmacology and Experimental Therapeutics