BRCA2 is needed for both repair and cell cycle arrest in mammalian cells exposed to S23906, an anticancer monofunctional DNA binder

Repair of DNA-targeted anticancer agents is an active area of investigation of both fundamental and clinical interest. However, most studies have focused on a small number of compounds limiting our understanding of both DNA repair and the DNA damage response. {"type":"entrez-protein","attrs":{"text":"S23906","term_id":"96914","term_text":"pir||S23906"}}S23906 is an acronycine derivative that shows strong activity toward solid tumors in experimental models. {"type":"entrez-protein","attrs":{"text":"S23906","term_id":"96914","term_text":"pir||S23906"}}S23906 forms bulky monofunctional DNA adducts in the minor groove which leads to destabilization of the double-stranded helix. We now report that {"type":"entrez-protein","attrs":{"text":"S23906","term_id":"96914","term_text":"pir||S23906"}}S23906 induces formation of DNA double strand breaks that are processed through homologous recombination (HR) but not Non-Homologous End-Joining (NHEJ) repair. Interestingly, {"type":"entrez-protein","attrs":{"text":"S23906","term_id":"96914","term_text":"pir||S23906"}}S23906 exposure was accompanied by a higher sensitivity of BRCA2-deficient cells compared to other HR deficient cell lines and by an S-phase accumulation in wild-type (wt), but not in BRCA2-deficient cells. Recently, we have shown that {"type":"entrez-protein","attrs":{"text":"S23906","term_id":"96914","term_text":"pir||S23906"}}S23906-induced S phase arrest was mediated by the checkpoint kinase Chk1. However, its activated phosphorylated form is equally induced by {"type":"entrez-protein","attrs":{"text":"S23906","term_id":"96914","term_text":"pir||S23906"}}S23906 in wt and BRCA2-deficient cells, likely indicating a role for BRCA2 downstream of Chk1. Accordingly, override of the S phase arrest by either 7-hydroxystaurosporine (UCN-01) or AZD7762 potentiates the cytotoxic activity of {"type":"entrez-protein","attrs":{"text":"S23906","term_id":"96914","term_text":"pir||S23906"}}S23906 in wt, but not in BRCA2-deficient cells. Together, our findings suggest that the pronounced sensitivity of BRCA2-deficient cells to {"type":"entrez-protein","attrs":{"text":"S23906","term_id":"96914","term_text":"pir||S23906"}}S23906 is due to both a defective S-phase arrest and the absence of HR repair. Tumors with deficiencies for proteins involved in HR, and BRCA2 in particular, may thus show increased sensitivity to {"type":"entrez-protein","attrs":{"text":"S23906","term_id":"96914","term_text":"pir||S23906"}}S23906, thereby providing a rationale for patient selection in clinical trials.