Cancer cells use self-inflicted DNA breaks to evade growth limits imposed by genotoxic stress.

Larsen BD, Benada J, Yung PYK, Bell RAV, Pappas G, Urban V, Ahlskog JK, Kuo TT, Janscak P, Megeney LA, Elsässer SJ, Bartek J, Sørensen CS

Science 376 (6592) 476-483 [2022-04-29; online 2022-04-28]

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.

Bioinformatics Support for Computational Resources [Service]

PubMed 35482866

DOI 10.1126/science.abi6378

Crossref 10.1126/science.abi6378

Publications 9.5.0