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

0557631 - ÚMG 2023 RIV US eng J - Journal Article
Larsen, B. - Benada, J. - Yung, P. - Bell, R. - Pappas, G. - Urban, Václav - Ahlskog, J. - Kuo, T. - Janščák, Pavel - Megeney, L. - Elsaesser, S. - Bártek, Jiří - Sorensen, C.S.
Cancer cells use self-inflicted DNA breaks to evade growth limits imposed by genotoxic stress.
Science. Roč. 376, č. 6592 (2022), s. 476-483. ISSN 0036-8075. E-ISSN 1095-9203
R&D Projects: GA ČR GA19-07674S
Institutional support: RVO:68378050
Keywords : caspase-activated dnase * cycle checkpoint * gene-expression * strand breaks * genome * inhibition * damage * death * phosphorylation * differentiation
OECD category: Genetics and heredity (medical genetics to be 3)
Impact factor: 56.9, year: 2022
Method of publishing: Limited access
https://www.science.org/doi/10.1126/science.abi6378

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.
Permanent Link: http://hdl.handle.net/11104/0331729