{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T15:17:26Z","timestamp":1788967046906,"version":"build-2803163510"},"reference-count":71,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T00:00:00Z","timestamp":1750809600000},"content-version":"vor","delay-in-days":5,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01GM144399"],"award-info":[{"award-number":["R01GM144399"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01CA285515"],"award-info":[{"award-number":["R01CA285515"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Center for Healthy Aging"},{"name":"Stony Brook University OVPR research"},{"name":"Renaissance School of Medicine"},{"name":"American Cancer Society Institutional Research"},{"name":"Stony Brook Cancer Center"},{"name":"NIH Shared Instrument Grant","award":["S10 OD021525-01"],"award-info":[{"award-number":["S10 OD021525-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,6,20]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Exacerbating the DNA replication problems of cancer cells serves as a viable therapeutic approach. Nevertheless, the cytotoxicity of cancer drugs is often hampered by therapy-induced senescence, leading to unfavorable patient outcomes. Here, we employ acute replisome dysfunction in combination with Ataxia telangiectasia and Rad3-related (ATR)\u00a0inhibition as a strategy to divert senescent cells toward death by triggering DNA replication catastrophe, a form of irreversible replication fork collapse caused by excessive single-stranded DNA (ssDNA) accumulation. RNA-sequencing revealed a distinct set of p53-responsive genes responsible for death. We identify c-Jun N-terminal kinase (JNK) to be essential for augmenting p53-dependent apoptotic programs and inducing pan-nuclear distribution of \u03b3H2AX, together constituting a feed-forward loop to drive cell death. Activation of DNA-PKcs initiates the signaling cascade of replication catastrophe, including CHK1-dependent JNK activation, which relies on MRE11 and PARP1 to expand and recognize ssDNA gaps, defining replication-associated gaps as an underlying basis for replication catastrophe. Our study elucidates the dynamic regulation of proximal and distal effectors along the DNA-PKcs\/JNK\/p53 axis that govern the cell fate decision between senescence and death. We propose that key determinants of replication catastrophe signaling are targetable vulnerabilities that can be exploited to limit senescent cell populations and increase the efficacy of anti-cancer therapies.<\/jats:p>","DOI":"10.1093\/nar\/gkaf573","type":"journal-article","created":{"date-parts":[[2025,6,25]],"date-time":"2025-06-25T10:20:22Z","timestamp":1750846822000},"source":"Crossref","is-referenced-by-count":9,"title":["The DNA-PKcs\/JNK\/p53 pathway underlies changes in cell fate decision toward death during DNA replication catastrophe"],"prefix":"10.1093","volume":"53","author":[{"given":"Jinal\u00a0A","family":"Patel","sequence":"first","affiliation":[{"name":"State University of New York at Stony Brook Department of Pharmacological Sciences, , Stony Brook , NY 11794 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Rageul","sequence":"additional","affiliation":[{"name":"State University of New York at Stony Brook Department of Pharmacological Sciences, , Stony Brook , NY 11794 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Lo","sequence":"additional","affiliation":[{"name":"State University of New York at Stony Brook Department of Pharmacological Sciences, , Stony Brook , NY 11794 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Auntara","family":"Nandi","sequence":"additional","affiliation":[{"name":"State University of New York at Stony Brook Department of Pharmacological Sciences, , Stony Brook , NY 11794 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camryn","family":"Zezelic","sequence":"additional","affiliation":[{"name":"State University of New York at Stony Brook Department of Pharmacological Sciences, , Stony Brook , NY 11794 ,","place":["United 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