{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T18:48:39Z","timestamp":1782499719156,"version":"3.54.5"},"update-to":[{"DOI":"10.1371\/journal.pgen.1012213","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:00:00Z","timestamp":1782432000000}}],"reference-count":55,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM144307"],"award-info":[{"award-number":["R35GM144307"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    Ataxia telangiectasia and Rad3-related (ATR) initiates cell cycle checkpoints to maintain genome integrity in the presence of replication stress or various forms of DNA damage. However, how ATR is activated for checkpoint initiation remains incompletely understood. The canonical model suggests that binding of an ATR-activator protein relieves the autoinhibitory PIKK regulatory domain (PRD) within the kinase domain, thereby activating ATR by granting substrate access to the catalytic centre. To better understand the checkpoint initiation mechanism, we conducted a genetic screen in fission yeast that identified a charge-reversal mutation, E1369K, in the conserved FRAP-ATM-TRRAP (FAT) domain of Rad3, the ortholog of ATR.\n                    <jats:italic>In vitro<\/jats:italic>\n                    kinase assays show that the mutation converts Rad3 into a constitutively active form. This allows rescue of the Rad3 kinase signaling defect in cells lacking the phosphorylation of the Rad9-Rad1-Hus1 (9-1-1) complex specifically in the DNA replication checkpoint, not the damage checkpoint pathway. Since the mutation is not in the kinase domain and is away from the PRD, these findings show that, in addition to the canonical mechanism, Rad3 may also be activated allosterically via the FAT domain, a mechanism likely conserved in higher eukaryotes.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1012213","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T17:55:29Z","timestamp":1782150929000},"page":"e1012213","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["A point mutation in the FAT domain constitutively increases the kinase activity of Rad3ATR and bypasses the requirement for 9-1\u20131 phosphorylation to activate the DNA replication checkpoint"],"prefix":"10.1371","volume":"22","author":[{"given":"Kamal","family":"Dev","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5792-3768","authenticated-orcid":true,"given":"S. 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