{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T17:08:40Z","timestamp":1789664920130,"version":"4.0.1"},"reference-count":59,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,6]],"date-time":"2022-07-06T00:00:00Z","timestamp":1657065600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"BMBF","award":["02NUK037B"],"award-info":[{"award-number":["02NUK037B"]}]},{"name":"BMBF","award":["02NUK043B"],"award-info":[{"award-number":["02NUK043B"]}]},{"name":"BMBF","award":["02NUK054B"],"award-info":[{"award-number":["02NUK054B"]}]},{"name":"BMBF","award":["DFG GRK1739"],"award-info":[{"award-number":["DFG GRK1739"]}]},{"name":"BMBF","award":["GRK1739"],"award-info":[{"award-number":["GRK1739"]}]},{"DOI":"10.13039\/501100001659","name":"DFG","doi-asserted-by":"publisher","award":["02NUK037B"],"award-info":[{"award-number":["02NUK037B"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"DFG","doi-asserted-by":"publisher","award":["02NUK043B"],"award-info":[{"award-number":["02NUK043B"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"DFG","doi-asserted-by":"publisher","award":["02NUK054B"],"award-info":[{"award-number":["02NUK054B"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"DFG","doi-asserted-by":"publisher","award":["DFG GRK1739"],"award-info":[{"award-number":["DFG GRK1739"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"DFG","doi-asserted-by":"publisher","award":["GRK1739"],"award-info":[{"award-number":["GRK1739"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The intra-S-phase checkpoint was among the first reported cell cycle checkpoints in mammalian cells. It transiently slows down the rate of DNA replication after DNA damage to facilitate repair and thus prevents genomic instability. The ionizing radiation (IR)-induced intra-S-phase checkpoint in mammalian cells is thought to be mainly dependent upon the kinase activity of ATM. Defects in the intra-S-phase checkpoint result in radio-resistant DNA synthesis (RDS), which promotes genomic instability. ATM belongs to the PI3K kinase family along with ATR and DNA-PKcs. ATR has been shown to be the key kinase for intra-S-phase checkpoint signaling in yeast and has also been implicated in this checkpoint in higher eukaryotes. Recently, contributions of DNA-PKcs to IR-induced G2-checkpoint could also be established. Whether and how ATR and DNA-PKcs are involved in the IR-induced intra-S-phase checkpoint in mammalian cells is incompletely characterized. Here, we investigated the contributions of ATM, ATR, and DNA-PKcs to intra-S-phase checkpoint activation after exposure to IR of human and hamster cells. The results suggest that the activities of both ATM and ATR are essential for efficient intra-S-phase checkpoint activation. Indeed, in a wild-type genetic background, ATR inhibition generates stronger checkpoint defects than ATM inhibition. Similar to G2 checkpoint, DNA-PKcs contributes to the recovery from the intra-S-phase checkpoint. DNA-PKcs\u2013deficient cells show persistent, mainly ATR-dependent intra-S-phase checkpoints. A correlation between the degree of DSB end resection and the strength of the intra-S-phase checkpoint is observed, which again compares well to the G2 checkpoint response. We conclude that the organization of the intra-S-phase checkpoint has a similar mechanistic organization to that of the G2 checkpoint in cells irradiated in the G2 phase.<\/jats:p>","DOI":"10.3390\/ijms23147506","type":"journal-article","created":{"date-parts":[[2022,7,6]],"date-time":"2022-07-06T09:41:10Z","timestamp":1657100470000},"page":"7506","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["ATR Contributes More Than ATM in Intra-S-Phase Checkpoint Activation after IR, and DNA-PKcs Facilitates Recovery: Evidence for Modular Integration of ATM\/ATR\/DNA-PKcs Functions"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9696-1006","authenticated-orcid":false,"given":"Aashish","family":"Soni","sequence":"first","affiliation":[{"name":"Division of Experimental Radiation Biology, Department of Radiation Therapy, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"},{"name":"Institute of Medical Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolu","family":"Duan","sequence":"additional","affiliation":[{"name":"Institute of Medical Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Stuschke","sequence":"additional","affiliation":[{"name":"Division of Experimental Radiation Biology, Department of Radiation Therapy, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"},{"name":"German Cancer Consortium (DKTK), Partner Site University Hospital Essen, and German Cancer Research Center (DKFZ), 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1152-5342","authenticated-orcid":false,"given":"George","family":"Iliakis","sequence":"additional","affiliation":[{"name":"Division of Experimental Radiation Biology, Department of Radiation Therapy, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"},{"name":"Institute of Medical Radiation Biology, University Hospital Essen, University of Duisburg-Essen, 45147 Essen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1821","DOI":"10.1126\/science.7997877","article-title":"Cell cycle control and cancer","volume":"266","author":"Hartwell","year":"1994","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5834","DOI":"10.1038\/sj.onc.1206682","article-title":"DNA damage checkpoint control in cells exposed to ionizing radiation","volume":"22","author":"Iliakis","year":"2003","journal-title":"Oncogene"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1682","DOI":"10.4161\/cc.6.14.4480","article-title":"An Imperfect G2\/M Checkpoint Contributes to Chromosome Instability Following Irradiation of S and G2 Phase Cells","volume":"6","author":"Krempler","year":"2007","journal-title":"Cell Cycle"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"103076","DOI":"10.1016\/j.dnarep.2021.103076","article-title":"Proficiency in homologous recombination repair is prerequisite for activation of G2-checkpoint at low radiation doses","volume":"101","author":"Soni","year":"2021","journal-title":"DNA Repair"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"11292","DOI":"10.1158\/0008-5472.CAN-05-2148","article-title":"Checkpoint Abrogation in G2 Compromises Repair of Chromosomal Breaks in Ataxia Telangiectasia Cells","volume":"65","author":"Terzoudi","year":"2005","journal-title":"Cancer Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1038\/nature03097","article-title":"Cell-cycle checkpoints and cancer","volume":"432","author":"Kastan","year":"2004","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1016\/j.radonc.2012.01.005","article-title":"DNA damage by X-rays and their impact on replication processes","volume":"102","author":"Parplys","year":"2012","journal-title":"Radiother. 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