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Cancer cells use self-inflicted DNA breaks to evade growth limits imposed by genotoxic stress
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SYSNO ASEP 0557631 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Cancer cells use self-inflicted DNA breaks to evade growth limits imposed by genotoxic stress Author(s) Larsen, B. (DK)
Benada, J. (DK)
Yung, P. (SE)
Bell, R. (CA)
Pappas, G. (DK)
Urban, Václav (UMG-J)
Ahlskog, J. (DK)
Kuo, T. (DK)
Janščák, Pavel (UMG-J) RID
Megeney, L. (CA)
Elsaesser, S. (SE)
Bártek, Jiří (UMG-J) RID
Sorensen, C.S. (DK)Number of authors 13 Source Title Science. - : American Association for the Advancement of Science - ISSN 0036-8075
Roč. 376, č. 6592 (2022), s. 476-483Number of pages 8 s. Publication form Online - E Language eng - English Country US - United States Keywords caspase-activated dnase ; cycle checkpoint ; gene-expression ; strand breaks ; genome ; inhibition ; damage ; death ; phosphorylation ; differentiation Subject RIV EB - Genetics ; Molecular Biology OECD category Genetics and heredity (medical genetics to be 3) R&D Projects GA19-07674S GA ČR - Czech Science Foundation (CSF) Method of publishing Limited access Institutional support UMG-J - RVO:68378050 UT WOS 000791247600068 DOI 10.1126/science.abi6378 Annotation 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. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2023 Electronic address https://www.science.org/doi/10.1126/science.abi6378
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