{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T21:38:17Z","timestamp":1791581897320,"version":"4.3.4"},"reference-count":82,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:00:00Z","timestamp":1781136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010537","name":"Nebraska Department of Health and Human Services","doi-asserted-by":"publisher","award":["2022-42"],"award-info":[{"award-number":["2022-42"]}],"id":[{"id":"10.13039\/100010537","id-type":"DOI","asserted-by":"publisher"}]},{"award":["2022-42"],"award-info":[{"award-number":["2022-42"]}],"id":[{"id":"https:\/\/ror.org\/03m7azy07","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA206444"],"award-info":[{"award-number":["R01CA206444"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"award":["R01CA206444"],"award-info":[{"award-number":["R01CA206444"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01GM143329"],"award-info":[{"award-number":["R01GM143329"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P30GM106397"],"award-info":[{"award-number":["P30GM106397"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"award":["R01GM143329"],"award-info":[{"award-number":["R01GM143329"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P30GM106397"],"award-info":[{"award-number":["P30GM106397"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Pancreatic ductal adenocarcinomas (PDACs) are lethal tumors exhibiting resistance to most cancer therapeutics, particularly DNA-damaging agents. The KRAS oncogene drives PDACs, and many of these tumors are addicted to it and its downstream effectors. One such effector is Rac1, a small GTPase involved in actin cytoskeleton remodeling and regulation of the DNA damage response. We previously showed that Rac1 inhibition blocks activation of ATM\/Chk2 and ATR\/Chk1 pathways in response to gamma rays, sensitizing PDAC cells to radiation. Methods: Western blot analyses were used to assess the impacts of Rac1 inhibition on the components of the ATR\/Chk1 cascade. Results: Here, we show that Rac1 inhibition disrupts ATR\/Chk1 signaling by promoting degradation of Claspin, a key component of the fork protection complex needed for the Ser345-phosphorylation of Chk1 by ATR. In PDACs and normal pancreatic ductal cells, Rac1 inhibition (via inhibitors or siRNA) decreased Claspin protein levels without affecting its mRNA, reflecting a &gt;3-fold reduction in Claspin\u2019s half-life. Claspin contains a phosphodegron recognized by SCF\u03b2TrCP E3 ubiquitin ligase when phosphorylated at Ser30\/Ser34, a process involving PLK1 kinase. In PDAC cells, Claspin degradation upon Rac1 inhibition required the proteasome and \u03b2TrCP1\/2 proteins, and was blocked by the mutagenesis of Ser30\/Ser34, but occurred independently of PLK1 activity. Although Rac1 inhibitors reduced Claspin in both normal and cancer cells, PDAC cells may be uniquely vulnerable due to elevated replication stress and greater reliance on ATR\/Chk1. Accordingly, Claspin depletion sensitized PDAC cells but not normal cells to gamma rays, inducing apoptosis only in cancer cells. Conclusions: These findings identify Rac1 as a critical regulator of ATR\/Chk1 signaling through stabilization of the fork protection protein Claspin. Rac1 inhibition promotes the \u03b2TrCP-dependent, proteasome-mediated degradation of Claspin via its phosphodegron, thereby impairing Chk1 activation in response to DNA damage.<\/jats:p>","DOI":"10.3390\/cancers18121908","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T01:52:08Z","timestamp":1781229128000},"page":"1908","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Rac1 GTPase Regulates the SCF\u03b2TrCP-Mediated Degradation of Claspin and the Cellular Response of Pancreatic Cancer Cells to Gamma Rays"],"prefix":"10.3390","volume":"18","author":[{"given":"Neha","family":"Chaudhary","sequence":"first","affiliation":[{"name":"Department Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA"},{"name":"Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tabbatha N.","family":"Somers","sequence":"additional","affiliation":[{"name":"Department Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9470-9317","authenticated-orcid":false,"given":"Surinder K.","family":"Batra","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3546-3991","authenticated-orcid":false,"given":"Ying","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, University of Nebraska Medical Center, Omaha, NE 68198, USA"},{"name":"Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7265-6779","authenticated-orcid":false,"given":"Michel M.","family":"Ouellette","sequence":"additional","affiliation":[{"name":"Department Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA"},{"name":"Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1242\/jcs.01118","article-title":"Rho-family GTPases: It\u2019s not only Rac and Rho (and I like it)","volume":"117","author":"Wennerberg","year":"2004","journal-title":"J. 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