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ATR inhibitors (ATRi) are in clinical development for treating various cancers, including those with high replication stress, such as is elicited by ARID1A deficiency, but the cellular mechanisms that determine ATRi efficacy in such backgrounds are unclear. Here, we have conducted unbiased genome-scale CRISPR screens in\n                    <jats:italic>ARID1A<\/jats:italic>\n                    -deficient and proficient cells treated with ATRi. We found that loss of transcription factor KLF5 has severe negative impact on fitness of\n                    <jats:italic>ARID1A<\/jats:italic>\n                    -deficient cells while hypersensitising\n                    <jats:italic>ARID1A<\/jats:italic>\n                    -proficient cells to ATRi. KLF5 loss induced replication stress, DNA damage, increased DNA-RNA hybrid formation, and genomic instability upon ATR inhibition. Mechanistically, we show that KLF5 protects cells from replication stress, at least in part through regulating BRD4 recruitment to chromatin. Overall, our work identifies KLF5 as a potential target for eradicating\n                    <jats:italic>ARID1A<\/jats:italic>\n                    -deficient cancers.\n                  <\/jats:p>","DOI":"10.1038\/s41467-024-55637-5","type":"journal-article","created":{"date-parts":[[2025,1,8]],"date-time":"2025-01-08T05:44:02Z","timestamp":1736315042000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["KLF5 loss sensitizes cells to ATR inhibition and is synthetic lethal with ARID1A deficiency"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4328-8601","authenticated-orcid":false,"given":"Samah W.","family":"Awwad","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colm","family":"Doyle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josie","family":"Coulthard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5760-5113","authenticated-orcid":false,"given":"Aldo S.","family":"Bader","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadia","family":"Gueorguieva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4476-0971","authenticated-orcid":false,"given":"Simon","family":"Lam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vipul","family":"Gupta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rimma","family":"Belotserkovskaya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tuan-Anh","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shankar","family":"Balasubramanian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9317-7937","authenticated-orcid":false,"given":"Stephen P.","family":"Jackson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,8]]},"reference":[{"key":"55637_CR1","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1038\/ncb2897","volume":"16","author":"MK Zeman","year":"2014","unstructured":"Zeman, M. 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