{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T21:04:01Z","timestamp":1791320641980,"version":"4.3.1"},"reference-count":31,"publisher":"Rockefeller University Press","issue":"3","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,3,12]]},"abstract":"<jats:p>Replicative stress (RS) is a type of endogenous DNA damage that cells suffer every time they duplicate their genomes, and which is further boosted by oncogenes. In mammals, the RS response (RSR) is coordinated by ATR and Chk1 kinases. We sought to develop a mammalian organism that is selectively protected from RS. To this end, mice carrying an extra copy of the Chk1 gene were generated. In vitro, Chk1 transgenic cells are protected from RS-inducing agents. Moreover, an extra Chk1 allele prolongs the survival of ATR-Seckel mice, which suffer from high levels of RS, but not that of ATM-deficient mice, which accumulate DNA breaks. Surprisingly, increased Chk1 levels favor transformation, which we show is associated with a reduction in the levels of RS induced by oncogenes. Our study provides the first example where supra-physiological levels of a tumor suppressor can promote malignant transformation, which is a result of the protection from the RS found in cancer cells.<\/jats:p>","DOI":"10.1084\/jem.20112147","type":"journal-article","created":{"date-parts":[[2012,2,28]],"date-time":"2012-02-28T00:01:44Z","timestamp":1330387304000},"page":"455-461","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":115,"title":["An extra allele of Chk1 limits oncogene-induced replicative stress and promotes transformation"],"prefix":"10.1084","volume":"209","author":[{"given":"Andres J.","family":"L\u00f3pez-Contreras","sequence":"first","affiliation":[{"name":"Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula","family":"Gutierrez-Martinez","sequence":"additional","affiliation":[{"name":"Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Specks","sequence":"additional","affiliation":[{"name":"Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Rodrigo-Perez","sequence":"additional","affiliation":[{"name":"Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar","family":"Fernandez-Capetillo","sequence":"additional","affiliation":[{"name":"Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2012,2,27]]},"reference":[{"key":"2023072601032753700_bib1","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/S0092-8674(00)80086-0","article-title":"Atm-deficient mice: a paradigm of ataxia telangiectasia","volume":"86","author":"Barlow","year":"1996","journal-title":"Cell."},{"key":"2023072601032753700_bib2","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1038\/nature10275","article-title":"A continuum model for tumour suppression","volume":"476","author":"Berger","year":"2011","journal-title":"Nature."},{"key":"2023072601032753700_bib3","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1016\/j.cell.2011.03.044","article-title":"Nucleotide deficiency promotes genomic instability in early stages of cancer development","volume":"145","author":"Bester","year":"2011","journal-title":"Cell."},{"key":"2023072601032753700_bib4","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1101\/gad.14.4.397","article-title":"ATR disruption leads to chromosomal fragmentation and early embryonic lethality","volume":"14","author":"Brown","year":"2000","journal-title":"Genes Dev."},{"key":"2023072601032753700_bib5","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1038\/nrm2450","article-title":"ATR: an essential regulator of genome integrity","volume":"9","author":"Cimprich","year":"2008","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2023072601032753700_bib6","doi-asserted-by":"publisher","first-page":"1713","DOI":"10.1126\/science.1065521","article-title":"ATR and ATRIP: partners in checkpoint signaling","volume":"294","author":"Cortez","year":"2001","journal-title":"Science."},{"key":"2023072601032753700_bib7","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1084\/jem.20051923","article-title":"ATM regulates ATR chromatin loading in response to DNA double-strand breaks","volume":"203","author":"Cuadrado","year":"2006","journal-title":"J. Exp. Med."},{"key":"2023072601032753700_bib8","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1016\/S0960-9822(00)00447-4","article-title":"Targeted disruption of the cell-cycle checkpoint gene ATR leads to early embryonic lethality in mice","volume":"10","author":"de Klein","year":"2000","journal-title":"Curr. Biol."},{"key":"2023072601032753700_bib9","doi-asserted-by":"publisher","first-page":"6225","DOI":"10.1093\/emboj\/cdf595","article-title":"\u201cSuper p53\u201d mice exhibit enhanced DNA damage response, are tumor resistant and age normally","volume":"21","author":"Garc\u00eda-Cao","year":"2002","journal-title":"EMBO J."},{"key":"2023072601032753700_bib10","doi-asserted-by":"publisher","first-page":"9693","DOI":"10.1158\/0008-5472.CAN-10-2286","article-title":"Combining ATR suppression with oncogenic Ras synergistically increases genomic instability, causing synthetic lethality or tumorigenesis in a dosage-dependent manner","volume":"70","author":"Gilad","year":"2010","journal-title":"Cancer Res."},{"key":"2023072601032753700_bib11","doi-asserted-by":"publisher","first-page":"1352","DOI":"10.1126\/science.1140735","article-title":"An oncogene-induced DNA damage model for cancer development","volume":"319","author":"Halazonetis","year":"2008","journal-title":"Science."},{"key":"2023072601032753700_bib12","doi-asserted-by":"publisher","first-page":"7067","DOI":"10.1158\/1078-0432.CCR-11-1198","article-title":"Therapeutic implications for the induced levels of Chk1 in Myc-expressing cancer cells","volume":"17","author":"H\u00f6glund","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"2023072601032753700_bib13","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.1038\/nature08467","article-title":"The DNA-damage response in human biology and disease","volume":"461","author":"Jackson","year":"2009","journal-title":"Nature."},{"key":"2023072601032753700_bib14","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1038\/ncb1337","article-title":"ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks","volume":"8","author":"Jazayeri","year":"2006","journal-title":"Nat. Cell Biol."},{"key":"2023072601032753700_bib15","doi-asserted-by":"publisher","first-page":"2011","DOI":"10.1101\/gad.169037","article-title":"Mechanisms and pathways of growth failure in primordial dwarfism","volume":"25","author":"Klingseisen","year":"2011","journal-title":"Genes Dev."},{"key":"2023072601032753700_bib16","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.ccr.2004.06.015","article-title":"Chk1 is haploinsufficient for multiple functions critical to tumor suppression","volume":"6","author":"Lam","year":"2004","journal-title":"Cancer Cell."},{"key":"2023072601032753700_bib17","doi-asserted-by":"publisher","first-page":"1448","DOI":"10.1101\/gad.14.12.1448","article-title":"Chk1 is an essential kinase that is regulated by Atr and required for the G(2)\/M DNA damage checkpoint","volume":"14","author":"Liu","year":"2000","journal-title":"Genes Dev."},{"key":"2023072601032753700_bib18","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1038\/nrc2248","article-title":"The impact of a negligent G2\/M checkpoint on genomic instability and cancer induction","volume":"7","author":"L\u00f6brich","year":"2007","journal-title":"Nat. Rev. Cancer."},{"key":"2023072601032753700_bib19","doi-asserted-by":"publisher","first-page":"1249","DOI":"10.1016\/j.dnarep.2010.09.012","article-title":"The ATR barrier to replication-born DNA damage","volume":"9","author":"L\u00f3pez-Contreras","year":"2010","journal-title":"DNA Repair"},{"key":"2023072601032753700_bib20","doi-asserted-by":"publisher","first-page":"2736","DOI":"10.1101\/gad.310304","article-title":"Increased gene dosage of Ink4a\/Arf results in cancer resistance and normal aging","volume":"18","author":"Matheu","year":"2004","journal-title":"Genes Dev."},{"key":"2023072601032753700_bib21","doi-asserted-by":"publisher","first-page":"1160","DOI":"10.1126\/science.1140321","article-title":"ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage","volume":"316","author":"Matsuoka","year":"2007","journal-title":"Science."},{"key":"2023072601032753700_bib22","doi-asserted-by":"publisher","first-page":"891","DOI":"10.1038\/ng.420","article-title":"A mouse model of ATR-Seckel shows embryonic replicative stress and accelerated aging","volume":"41","author":"Murga","year":"2009","journal-title":"Nat. Genet."},{"key":"2023072601032753700_bib23","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1038\/nsmb.2189","article-title":"Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors","volume":"18","author":"Murga","year":"2011","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2023072601032753700_bib24","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1038\/ng1129","article-title":"A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome","volume":"33","author":"O\u2019Driscoll","year":"2003","journal-title":"Nat. Genet."},{"key":"2023072601032753700_bib25","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/j.stem.2007.03.002","article-title":"Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss","volume":"1","author":"Ruzankina","year":"2007","journal-title":"Cell Stem Cell."},{"key":"2023072601032753700_bib26","doi-asserted-by":"publisher","first-page":"1144","DOI":"10.1038\/ng.441","article-title":"Tissue regenerative delays and synthetic lethality in adult mice after combined deletion of Atr and Trp53","volume":"41","author":"Ruzankina","year":"2009","journal-title":"Nat. Genet."},{"key":"2023072601032753700_bib27","doi-asserted-by":"publisher","first-page":"1749","DOI":"10.1126\/science.7792600","article-title":"A single ataxia telangiectasia gene with a product similar to PI-3 kinase","volume":"268","author":"Savitsky","year":"1995","journal-title":"Science."},{"key":"2023072601032753700_bib28","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1172\/JCI58928","article-title":"Oncogenic stress sensitizes murine cancers to hypomorphic suppression of ATR","volume":"122","author":"Schoppy","year":"2012","journal-title":"J. Clin. Invest."},{"key":"2023072601032753700_bib29","doi-asserted-by":"crossref","first-page":"1439","DOI":"10.1101\/gad.14.12.1439","article-title":"Aberrant cell cycle checkpoint function and early embryonic death in Chk1(-\/-) mice","volume":"14","author":"Takai","year":"2000","journal-title":"Genes Dev."},{"key":"2023072601032753700_bib30","doi-asserted-by":"publisher","first-page":"721","DOI":"10.1038\/nsmb.2076","article-title":"A cell-based screen identifies ATR inhibitors with synthetic lethal properties for cancer-associated mutations","volume":"18","author":"Toledo","year":"2011","journal-title":"Nat. Struct. Mol. Biol."},{"key":"2023072601032753700_bib31","doi-asserted-by":"publisher","first-page":"6574","DOI":"10.1158\/0008-5472.CAN-06-3545","article-title":"The E2F-regulated gene Chk1 is highly expressed in triple-negative estrogen receptor \/progesterone receptor \/HER-2 breast carcinomas","volume":"67","author":"Verlinden","year":"2007","journal-title":"Cancer Res."}],"container-title":["Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/209\/3\/455\/1744426\/jem_20112147.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/209\/3\/455\/1744426\/jem_20112147.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T21:03:52Z","timestamp":1690319032000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/209\/3\/455\/41320\/An-extra-allele-of-Chk1-limits-oncogene-induced"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,2,27]]},"references-count":31,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2012,3,12]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20112147","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.716197970.791552879","asserted-by":"object"}]},"ISSN":["1540-9538","0022-1007"],"issn-type":[{"value":"1540-9538","type":"electronic"},{"value":"0022-1007","type":"print"}],"subject":[],"published":{"date-parts":[[2012,2,27]]}}}