Abstract
RAD51 recombinase polymerizes at the site of double-strand breaks (DSBs) where it performs DSB repair. The loss of RAD51 causes extensive chromosomal breaks, leading to apoptosis. The polymerization of RAD51 is regulated by a number of RAD51 mediators, such as BRCA1, BRCA2, RAD52, SFR1, SWS1, and the five RAD51 paralogs, including XRCC3. We here show that brca2-null mutant cells were able to proliferate, indicating that RAD51 can perform DSB repair in the absence of BRCA2. We disrupted the BRCA1, RAD52, SFR1, SWS1, and XRCC3 genes in the brca2-null cells. All the resulting double-mutant cells displayed a phenotype that was very similar to that of the brca2-null cells. We suggest that BRCA2 might thus serve as a platform to recruit various RAD51 mediators at the appropriate position at the DNA–damage site.
Highlights
Homologous recombination (HR) maintains genome integrity by accurately repairing double-strand breaks (DSBs) that arise during the mitotic cell cycle or are induced by radiotherapy [1,2]
We conclude that SFR1 and SWS1 work as RAD51 mediators, though their contribution to HR-dependent repair is less significant than that of BRCA1, BRCA2, and the RAD51 paralogs
We show that BRCA2 plays a more important role in the promotion of both RAD51 polymerization at DNA-damage sites and HR-dependent repair than does any other RAD51 mediator, including BRCA1, the RAD51 paralogs, RAD52, SFR1, and SWS1
Summary
Homologous recombination (HR) maintains genome integrity by accurately repairing double-strand breaks (DSBs) that arise during the mitotic cell cycle or are induced by radiotherapy [1,2]. Effective HR makes tumor cells tolerant to the chemotherapeutic agents that damage DNA and stall replicative DNA polymerases. Such chemotherapeutic agents include cis-diaminedichloroplatinum(II) (cisplatin), camptothecin, and poly(ADP-ribose) polymerase (PARP) inhibitors, including olaparib (AstraZeneca). Cisplatin is a crosslinking agent that generates intra- and inter-strand crosslinks and thereby stalls replicative DNA polymerases. Since HR plays a major role in repairing DNA lesions generated by camptothecin, cisplatin, and PARP inhibitors [6], measuring HR efficiency in individual malignant tumors may help predict the efficacy of these chemotherapeutic treatment for each tumor [7,8,9]
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