Arsenic affects homologous recombination and single-strand annealing but not end-joining pathways during DNA double-strand break repair.

Arsenic is a carcinogen that can cause skin, lung, and bladder cancer. While DNA double-strand breaks (DSBs) have been implicated in arsenic-induced carcinogenesis, the exact mechanism remains unclear. In this study, we performed genetic analysis to examine the impact of arsenic trioxide on four different DSB repair pathways using the human pre-B cell line Nalm-6. Random integration analysis showed that arsenic trioxide does not negatively affect non-homologous end joining (NHEJ) or polymerase theta-mediated end-joining (TMEJ). In contrast, chromosomal DSB repair analysis revealed that arsenic trioxide decreases the efficiency of homologous recombination (HR) and, less prominently, single-strand annealing (SSA). Consistent with this finding, arsenic trioxide decreased gene-targeting efficiency, owing to a significant reduction in the frequency of HR-mediated targeted integration. To further verify the inhibitory effect of arsenic on HR, we examined cellular sensitivity to olaparib and camptothecin, which induce one-ended DSBs requiring HR for precise repair. Intriguingly, we found that arsenic trioxide significantly enhances sensitivity to those anticancer agents in HR-proficient cells. Our results suggest that arsenic-induced genomic instability is attributed to HR suppression, providing valuable insights into arsenic-associated carcinogenesis and therapeutic options.