title: Chk2 suppresses the oncogenic potential of DNA replication-associated DNA damage.
abstract: The Mre11 complex (Mre11, Rad50, and Nbs1) and Chk2 have been implicated in the DNA-damage response, an inducible process required for the suppression of malignancy. The Mre11 complex is predominantly required for repair and checkpoint activation in S phase, whereas Chk2 governs apoptosis. We examined the relationship between the Mre11 complex and Chk2 in the DNA-damage response via the establishment of Nbs1(DeltaB/DeltaB) Chk2(-/-) and Mre11(ATLD1/ATLD1) Chk2(-/-) mice. Chk2 deficiency did not modify the checkpoint defects or chromosomal instability of Mre11 complex mutants; however, the double-mutant mice exhibited synergistic defects in DNA-damage-induced p53 regulation and apoptosis. Nbs1(DeltaB/DeltaB) Chk2(-/-) and Mre11(ATLD1/ATLD1) Chk2(-/-) mice were also predisposed to tumors. In contrast, DNA-PKcs-deficient mice, in which G1-specific chromosome breaks are present, did not exhibit synergy with Chk2(-/-) mutants. These data suggest that Chk2 suppresses the oncogenic potential of DNA damage arising during S and G2 phases of the cell cycle.
authors.affiliation: Molecular Biology Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, Cornell University Graduate School of Medical Sciences, New York, NY 10021, USA.
authors.forename: Travis H
authors.initials: TH
authors.lastname: Stracker
authors.forename: Suzana S
authors.initials: SS
authors.lastname: Couto
authors.forename: Carlos
authors.initials: C
authors.lastname: Cordon-Cardo
authors.forename: Tulio
authors.initials: T
authors.lastname: Matos
authors.forename: John H J
authors.initials: JH
authors.lastname: Petrini
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D064447:Checkpoint Kinase 2; D043171:Chromosomal Instability; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000378:metabolism; D004261:DNA Replication; D018076:DNA, Complementary / Q000235:genetics; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005091:Exons / Q000235:genetics; D016678:Genome / Q000235:genetics; D000076228:MRE11 Homologue Protein; D051379:Mice; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000378:metabolism; D011230:Precancerous Conditions / Q000201:enzymology* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C417743:Cdkn2a protein, mouse; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C512689:Mre11a protein, mouse; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; D064447:Checkpoint Kinase 2; C578633:Chek2 protein, mouse; D051747:DNA-Activated Protein Kinase; C497264:Prkdc protein, mouse; D017346:Protein Serine-Threonine Kinases; D000076228:MRE11 Homologue Protein; D045643:DNA Repair Enzymes