DNA损伤
CTCF公司
染色质
癌细胞
生物
核酸酶
DNA
DNA修复
癌症
癌症研究
有丝分裂
细胞生物学
遗传学
转录因子
基因
增强子
作者
Brian D. Larsen,Jan Benada,Philip Yuk Kwong Yung,Robert Bell,George D. Pappas,Václav Urban,Johanna K. Ahlskog,Tia Tyrsett Kuo,Pavel Janscak,Lynn A. Megeney,Simon J. Elsässer,Jiří Bártek,Claus Storgaard Sørensen
出处
期刊:Science
[American Association for the Advancement of Science (AAAS)]
日期:2022-04-29
卷期号:376 (6592): 476-483
被引量:31
标识
DOI:10.1126/science.abi6378
摘要
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.
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