LAUSR

Genotoxic therapy such as radiation serves as a frontline cancer treatment, yet acquired resistance that leads to tumor reoccurrence is frequent. We found that cancer cells maintain viability during irradiation by reversibly increasing genome-wide DNA breaks, thereby limiting premature mitotic progression. We identify caspase-activated DNase (CAD) as the nuclease inflicting these de novo DNA lesions at defined loci, which are in proximity to chromatin-modifying CCCTC-binding factor (CTCF) sites. CAD nuclease activity is governed through phosphorylation by DNA damage response kinases, independent of caspase activity. In turn, loss of CAD activity impairs cell fate decisions, rendering cancer cells vulnerable to radiation-induced DNA double-strand breaks. Our observations highlight a cancer-selective survival adaptation, whereby tumor cells deploy regulated DNA breaks to delimit the detrimental effects of therapy-evoked DNA damage. Description Self-inflicted damage protects tumors Genotoxic treatments, such as radiation and some chemotherapy drugs, are a mainstay of cancer therapy, but they often fail to fully destroy tumor cells. Normal cells can protect themselves from genotoxic insults by activating the G1 cell cycle checkpoint, but this checkpoint is often dysfunctional in tumors. By contrast, Larsen et al. discovered that tumor cells can activate a nuclease that causes limited induction of DNA breaks at specific sites, which is coordinated with the process of DNA break repair. These self-inflicted DNA breaks trigger the G2 cell cycle checkpoint, preventing tumor cells from cycling and protecting them from death due to treatment-induced DNA damage. —YN Self-induced DNA breaks enforce the G2 checkpoint in tumors after ionizing radiation and promote cell survival.