title: Role of DNA damage response pathways in preventing carcinogenesis caused by intrinsic replication stress.
abstract: Defective DNA replication can result in genomic instability, cancer and developmental defects. To understand the roles of DNA damage response (DDR) genes on carcinogenesis in mutants defective for core DNA replication components, we utilized the Mcm4(Chaos3/Chaos3) ('Chaos3') mouse model that, by virtue of an amino-acid alteration in MCM4 that destabilizes the MCM2-7 DNA replicative helicase, has fewer dormant replication origins and an increased number of stalled replication forks. This leads to genomic instability and cancer in most Chaos3 mice. We found that animals doubly mutant for Chaos3 and components of the ataxia telangiectasia-mutated (ATM) double-strand break response pathway (Atm, p21/Cdkn1a and Chk2/Chek2) had decreased tumor latency and/or increased tumor susceptibility. Tumor latency and susceptibility differed between genetic backgrounds and genders, with females demonstrating an overall greater cancer susceptibility to Atm and p21 deficiency than males. Atm deficiency was semilethal in the Chaos3 background and impaired embryonic fibroblast proliferation, suggesting that ATM drug inhibitors might be useful against tumors with DNA replication defects. Hypomorphism for the 9-1-1 component Hus1 did not affect tumor latency or susceptibility in Chaos3 animals, and tumors in these mice did not exhibit impaired ATR pathway signaling. These and other data indicate that under conditions of systemic replication stress, the ATM pathway is particularly important both for cancer suppression and viability during development.
authors: 1] Department of Biomedical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, NY, USA [2] Department of Molecular Biology and Genetics, Ithaca, NY, USA.
authors: M D
authors: MD
authors: Wallace
authors: 1] Department of Biomedical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, NY, USA [2] Section of Anatomic Pathology, Ithaca, NY, USA.
authors: T L
authors: TL
authors: Southard
authors: Department of Biomedical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, NY, USA.
authors: K J
authors: KJ
authors: Schimenti
authors: 1] Department of Biomedical Sciences, Cornell University, College of Veterinary Medicine, Ithaca, NY, USA [2] Department of Molecular Biology and Genetics, Ithaca, NY, USA [3] Center for Vertebrate Genomics, Cornell University, Ithaca, NY, USA.
authors: J C
authors: JC
authors: Schimenti
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000172:deficiency; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D049109:Cell Proliferation; D064447:Checkpoint Kinase 2 / Q000172:deficiency; D004249:DNA Damage; D004261:DNA Replication / Q000235:genetics*; D004198:Disease Susceptibility / Q000473:pathology; D005260:Female; D008297:Male; D051379:Mice; D064148:Minichromosome Maintenance Complex Component 4 / Q000172:deficiency; D008954:Models, Biological; D015398:Signal Transduction / Q000235:genetics*; D054462:p21-Activated Kinases / Q000172:deficiency
chemical_list: D064447:Checkpoint Kinase 2; D064007:Ataxia Telangiectasia Mutated Proteins; C578633:Chek2 protein, mouse; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases; C516793:Mcm4 protein, mouse; D064148:Minichromosome Maintenance Complex Component 4
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