title: Defining ATM-Independent Functions of the Mre11 Complex with a Novel Mouse Model.
abstract: The Mre11 complex (Mre11, Rad50, and Nbs1) occupies a central node of the DNA damage response (DDR) network and is required for ATM activation in response to DNA damage. Hypomorphic alleles of MRE11 and NBS1 confer embryonic lethality in ATM-deficient mice, indicating that the complex exerts ATM-independent functions that are essential when ATM is absent. To delineate those functions, a conditional ATM allele (ATM(flox)) was crossed to hypomorphic NBS1 mutants (Nbs1(ΔB/ΔB) mice). Nbs1(ΔB/ΔB) Atm(-/-) hematopoietic cells derived by crossing to vav(cre) were viable in vivo. Nbs1(ΔB/ΔB) Atm(-/-) (VAV) mice exhibited a pronounced defect in double-strand break repair and completely penetrant early onset lymphomagenesis. In addition to repair defects observed, fragile site instability was noted, indicating that the Mre11 complex promotes genome stability upon replication stress in vivo. The data suggest combined influences of the Mre11 complex on DNA repair, as well as the responses to DNA damage and DNA replication stress.
  
  
  CONCLUSIONS
  A novel mouse model was developed, by combining a vav(cre)-inducible ATM knockout mouse with an NBS1 hypomorphic mutation, to analyze ATM-independent functions of the Mre11 complex in vivo. These data show that the DNA repair, rather than DDR signaling functions of the complex, is acutely required in the context of ATM deficiency to suppress genome instability and lymphomagenesis.
authors.affiliation: Molecular Biology Program, Sloan-Kettering Institute, New York, New York.
authors.forename: Alessia
authors.initials: A
authors.lastname: Balestrini
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Laura
authors.initials: L
authors.lastname: Nicolas
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Katherine
authors.initials: K
authors.lastname: Yang-Lott
authors.affiliation: Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Olga A
authors.initials: OA
authors.lastname: Guryanova
authors.affiliation: Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Abramson Family Cancer Research Institute, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Craig H
authors.initials: CH
authors.lastname: Bassing
authors.affiliation: Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jayanta
authors.initials: J
authors.lastname: Chaudhuri
authors.affiliation: Molecular Biology Program, Sloan-Kettering Institute, New York, New York. petrinij@mskcc.org.
authors.forename: John H J
authors.initials: JH
authors.lastname: Petrini
mesh_terms: D017668:Age of Onset; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D043283:Chromosome Fragile Sites; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004261:DNA Replication; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D008223:Lymphoma / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D045643:DNA Repair Enzymes