{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:56:51Z","timestamp":1782280611931,"version":"3.54.5"},"posted":{"date-parts":[[2025,1,18]]},"group-title":"Molecular Biology","reference-count":55,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,1,18]],"date-time":"2025-01-18T00:00:00Z","timestamp":1737158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,1,18]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>\n                  Integration of DNA replication with DNA repair, cell cycle progression, and other biological processes is crucial for preserving genome stability and fundamentally important for all life. Ataxia-telangiectasia mutated and RAD3-related (ATR) and its partner ATR-interacting protein (ATRIP) function as a critical proximal sensor and transducer of the DNA Damage Response (DDR). Several ATR substrates, including p53 and CHK1, are crucial for coordination of cell cycle phase transitions, transcription, and DNA repair when cells sustain DNA damage. While much is known about ATR activation mechanisms, it is less clear how ATR signaling is negatively regulated in cells. Here, we identify the DNA repair protein REV7 as a novel direct binding partner of ATRIP. We define a REV7-interaction motif in ATRIP, which when mutated abrogates the REV7-ATRIP interaction\n                  <jats:italic>in vitro<\/jats:italic>\n                  and in intact cells. Using\n                  <jats:italic>in vitro<\/jats:italic>\n                  kinase assays, we show that REV7 inhibits ATR-mediated phosphorylation of its substrates, including p53. Disruption of the REV7-ATRIP interaction also enhances phosphorylation of CHK1 at Ser317 (a known ATR target site) in intact cells. Taken together our results establish REV7 as a critical negative regulator of ATR signaling. REV7 has pleiotropic roles in multiple DDR pathways including Trans-Lesion Synthesis, DNA Double-Strand Break resection, and p53 stability and may play a central role in the integration of multiple genome maintenance pathways.\n                <\/jats:p>","DOI":"10.1101\/2025.01.17.633588","type":"posted-content","created":{"date-parts":[[2025,1,19]],"date-time":"2025-01-19T04:05:15Z","timestamp":1737259515000},"source":"Crossref","is-referenced-by-count":0,"title":["REV7 associates with ATRIP and inhibits ATR kinase activity"],"prefix":"10.64898","author":[{"given":"Megan","family":"Biller","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28223, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Kabir","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28223, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Nipper","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28223, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sydney","family":"Allen","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28223, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yara","family":"Kayali","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28223, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Skyler","family":"Kuncik","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28223, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Sasanuma","sequence":"additional","affiliation":[{"name":"Department of Genome Medicine, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Duke University School of Medicine, Durham, NC 27710 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyrus","family":"Vaziri","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA"},{"name":"Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junya","family":"Tomida","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, University of North Carolina at Charlotte, Charlotte, NC 28223, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041021534763000_2025.01.17.633588v1.1","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444906029799"},{"key":"2026041021534763000_2025.01.17.633588v1.2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.26.9.3527-3540.2006"},{"key":"2026041021534763000_2025.01.17.633588v1.3","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M501562200"},{"key":"2026041021534763000_2025.01.17.633588v1.4","doi-asserted-by":"publisher","DOI":"10.1080\/15384101.2024.2333227"},{"key":"2026041021534763000_2025.01.17.633588v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2017.05.015"},{"key":"2026041021534763000_2025.01.17.633588v1.6","doi-asserted-by":"crossref","unstructured":"Bluteau D , Masliah-Planchon J , Clairmont C , Rousseau A , Ceccaldi R , Dubois d\u2019Enghien C , Bluteau O , Cuccuini W , Gachet S , Peffault de Latour R et al (2016) Biallelic inactivation of REV7 is associated with Fanconi anemia. 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