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Given lagging clinical translation, we reexamined mechanisms and observed instead that DSB repair can proceed independently of DNA-PKcs. While repair of radiation-induced DSBs was blocked in cells expressing shRNAs targeting Ku proteins or other NHEJ core factors, DSBs were repaired on schedule despite targeting DNA-PKcs. Although we failed to observe a DSB repair defect, the \u03b3H2AX foci that formed at sites of DNA damage persisted indefinitely after irradiation, leading to cytokinesis failure and accumulation of binucleated cells. Following this mitotic slippage, cells with decreased DNA-PKcs underwent accelerated cellular senescence. We identified downregulation of ataxia-telangiectasia mutated kinase (ATM) as the critical role of DNA-PKcs in recovery from DNA damage, insofar as targeting ATM restored \u03b3H2AX foci resolution and cytokinesis. Considering the lack of direct impact on DSB repair and emerging links between senescence and resistance to cancer therapy, these results suggest reassessing DNA-PKcs as a target for cancer treatment.<\/jats:p>","DOI":"10.1242\/jcs.229385","type":"journal-article","created":{"date-parts":[[2019,6,12]],"date-time":"2019-06-12T13:25:23Z","timestamp":1560345923000},"source":"Crossref","is-referenced-by-count":20,"title":["Repair-independent functions of DNA-PKcs protect irradiated cells from mitotic slippage and accelerated senescence"],"prefix":"10.1242","volume":"132","author":[{"given":"Yue","family":"Liu","sequence":"first","affiliation":[{"name":"The University of Chicago Department of Molecular Genetics and Cell Biology and Ludwig Center for Metastasis Research , , 929 East 57th Street, Chicago, IL 60637 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena V.","family":"Efimova","sequence":"additional","affiliation":[{"name":"The University of Chicago Department of Molecular Genetics and Cell Biology and Ludwig Center for Metastasis Research , , 929 East 57th Street, Chicago, IL 60637 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aishwarya","family":"Ramamurthy","sequence":"additional","affiliation":[{"name":"The University of Chicago Department of Molecular Genetics and Cell Biology and Ludwig Center for Metastasis Research , , 929 East 57th Street, Chicago, IL 60637 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1518-2436","authenticated-orcid":false,"given":"Stephen J.","family":"Kron","sequence":"additional","affiliation":[{"name":"The University of Chicago Department of Molecular Genetics and Cell Biology and Ludwig Center for Metastasis Research , , 929 East 57th Street, Chicago, IL 60637 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2019,7,1]]},"reference":[{"key":"2024061318173603900_JCS229385C1","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1016\/j.dnarep.2004.04.013","article-title":"DSB repair: the yeast paradigm","volume":"3","author":"Aylon","year":"2004","journal-title":"DNA Repair"},{"key":"2024061318173603900_JCS229385C2","doi-asserted-by":"publisher","first-page":"1696","DOI":"10.1158\/1541-7786.MCR-11-0312","article-title":"Inhibition of DNA-dependent protein kinase induces accelerated senescence in irradiated human cancer cells","volume":"9","author":"Azad","year":"2011","journal-title":"Mol. 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