{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T00:53:38Z","timestamp":1780707218894,"version":"3.54.1"},"reference-count":64,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2023,5,5]],"date-time":"2023-05-05T00:00:00Z","timestamp":1683244800000},"content-version":"vor","delay-in-days":0,"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\/100000048","name":"American Cancer Society","doi-asserted-by":"publisher","award":["RSG-18-037-DMC"],"award-info":[{"award-number":["RSG-18-037-DMC"]}],"id":[{"id":"10.13039\/100000048","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001513","name":"Breast Cancer Alliance","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001513","id-type":"DOI","asserted-by":"publisher"}]},{"name":"American Cancer Society Institutional Research"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,7,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The structure of DNA replication forks is preserved by TIMELESS (TIM) in the fork protection complex (FPC) to support seamless fork progression. While the scaffolding role of the FPC to couple the replisome activity is much appreciated, the detailed mechanism whereby inherent replication fork damage is sensed and counteracted during DNA replication remains largely elusive. Here, we implemented an auxin-based degron system that rapidly triggers inducible proteolysis of TIM as a source of endogenous DNA replication stress and replisome dysfunction to dissect the signaling events that unfold at stalled forks. We demonstrate that acute TIM degradation activates the ATR-CHK1 checkpoint, whose inhibition culminates in replication catastrophe by single-stranded DNA accumulation and RPA exhaustion. Mechanistically, unrestrained replisome uncoupling, excessive origin firing, and aberrant reversed fork processing account for the synergistic fork instability. Simultaneous TIM loss and ATR inactivation triggers DNA-PK-dependent CHK1 activation, which is unexpectedly necessary for promoting fork breakage by MRE11 and catastrophic cell death. We propose that acute replisome dysfunction results in a hyper-dependency on ATR to activate local and global fork stabilization mechanisms to counteract irreversible fork collapse. Our study identifies TIM as a point of replication vulnerability in cancer that can be exploited with ATR inhibitors.<\/jats:p>","DOI":"10.1093\/nar\/gkad363","type":"journal-article","created":{"date-parts":[[2023,5,5]],"date-time":"2023-05-05T09:34:33Z","timestamp":1683279273000},"page":"6246-6263","source":"Crossref","is-referenced-by-count":13,"title":["Replisome dysfunction upon inducible TIMELESS degradation synergizes with ATR inhibition to trigger replication catastrophe"],"prefix":"10.1093","volume":"51","author":[{"given":"Jinal A","family":"Patel","sequence":"first","affiliation":[{"name":"Department of Pharmacological Sciences, State University of New York at Stony Brook , Stony Brook , NY \u00a011794, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camryn","family":"Zezelic","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences, State University of New York at Stony Brook , Stony Brook , NY \u00a011794, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Rageul","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences, State University of New York at Stony Brook , Stony Brook , NY \u00a011794, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Saldanha","sequence":"additional","affiliation":[{"name":"The Graduate program in Genetics, State University of New York at Stony Brook , Stony Brook , NY \u00a011794, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arafat","family":"Khan","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences, State University of New York at Stony Brook , Stony Brook , NY \u00a011794, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1913-6373","authenticated-orcid":false,"given":"Hyungjin","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pharmacological Sciences, State University of New York at Stony Brook , Stony Brook , NY \u00a011794, USA"},{"name":"Stony Brook Cancer Center, Renaissance School of Medicine at Stony Brook University , Stony Brook , NY \u00a011794, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,5,5]]},"reference":[{"key":"2023070701020053500_B1","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1038\/nrm2852","article-title":"Maintaining genome stability at the replication fork","volume":"11","author":"Branzei","year":"2010","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2023070701020053500_B2","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1038\/ncb2897","article-title":"Causes and consequences of replication stress","volume":"16","author":"Zeman","year":"2014","journal-title":"Nat. Cell Biol."},{"key":"2023070701020053500_B3","doi-asserted-by":"crossref","first-page":"2363","DOI":"10.1016\/j.molcel.2022.04.023","article-title":"Exploiting replication gaps for cancer therapy","volume":"82","author":"Cong","year":"2022","journal-title":"Mol. Cell"},{"key":"2023070701020053500_B4","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1038\/nrm2450","article-title":"ATR: an essential regulator of genome integrity","volume":"9","author":"Cimprich","year":"2008","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2023070701020053500_B5","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1038\/nrm.2017.67","article-title":"The essential kinase ATR: ensuring faithful duplication of a challenging genome","volume":"18","author":"Saldivar","year":"2017","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2023070701020053500_B6","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1101\/gad.214080.113","article-title":"ATR phosphorylates SMARCAL1 to prevent replication fork collapse","volume":"27","author":"Couch","year":"2013","journal-title":"Genes Dev."},{"key":"2023070701020053500_B7","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1038\/nsmb1267","article-title":"Role for BLM in replication-fork restart and suppression of origin firing after replicative stress","volume":"14","author":"Davies","year":"2007","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2023070701020053500_B8","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1016\/j.molcel.2015.07.029","article-title":"Distinct but concerted roles of ATR, DNA-PK, and Chk1 in countering replication stress during S phase","volume":"59","author":"Buisson","year":"2015","journal-title":"Mol. 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