hMSH5 facilitates the repair of camptothecin-induced double-strand breaks through an interaction with FANCJ [DNA and Chromosomes]

June 8th, 2015 by Xu, Y., Wu, X., Her, C.

Replication stress from stalled or collapsed replication forks is a major challenge to genomic integrity. The anticancer agent camptothecin (CPT) is a DNA topoisomerase I (Top I) inhibitor that causes fork collapse and double-strand breaks (DSBs) amid DNA replication. Here we report that hMSH5 promotes cell survival in response to CPT-induced DNA damage. Cells deficient in hMSH5 show elevated CPT-induced γ-H2AX and RPA2 foci with concomitant reduction of Rad51 foci, indicative of impaired homologous recombination (HR). In addition, CPT-treated hMSH5-deficient cells exhibit aberrant activation of Chk1 and Chk2 kinases, and therefore abnormal cell cycle progression. Furthermore, hMSH5 mediates chromatin recruitment of FANCJ, which underlies the effects of hMSH5 on HR and Chk1 activation. Intriguingly, FANCJ depletion desensitizes hMSH5-deficient cells to CPT-elicited cell killing. Collectively, our data point to the existence of a functional interplay between hMSH5 and FANCJ in DSB repair induced by replication stress.