López-Contreras, Andres JGutierrez-Martinez, PaulaSpecks, JuliaRodrigo-Perez, SaraFernandez-Capetillo, Oscar2024-02-092024-02-092012-03-12J Exp Med . 2012 ;209(3):455-61.http://hdl.handle.net/20.500.12105/17683Replicative 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.engVoRhttp://creativecommons.org/licenses/by-nc-nd/4.0/AllelesAnimalsAtaxia Telangiectasia Mutated ProteinsCell Cycle ProteinsCell Transformation, NeoplasticCheckpoint Kinase 1DNA DamageDNA-Binding ProteinsDwarfismFaciesGene DosageMiceMice, KnockoutMice, Mutant StrainsMice, TransgenicMicrocephalyOncogenesProtein KinasesProtein Serine-Threonine KinasesTumor Suppressor ProteinsAttribution-NonCommercial-NoDerivatives 4.0 Internacional22370720209345510.1084/jem.201121471540-9538The Journal of experimental medicineopen access