title: An extra allele of Chk1 limits oncogene-induced replicative stress and promotes transformation.
abstract: 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.
authors.affiliation: Genomic Instability Group, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain.
authors.forename: Andres J
authors.initials: AJ
authors.lastname: López-Contreras
authors.forename: Paula
authors.initials: P
authors.lastname: Gutierrez-Martinez
authors.forename: Julia
authors.initials: J
authors.lastname: Specks
authors.forename: Sara
authors.initials: S
authors.lastname: Rodrigo-Perez
authors.forename: Oscar
authors.initials: O
authors.lastname: Fernandez-Capetillo
mesh_terms: D000483:Alleles; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D000071877:Checkpoint Kinase 1; D004249:DNA Damage / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004392:Dwarfism / Q000235:genetics / Q000473:pathology; D019066:Facies; D018628:Gene Dosage; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008831:Microcephaly / Q000235:genetics / Q000473:pathology; D009857:Oncogenes; D011494:Protein Kinases / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D011494:Protein Kinases; C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D000071877:Checkpoint Kinase 1; C000605869:Chek1 protein, mouse; D017346:Protein Serine-Threonine Kinases