title: A murine model of Nijmegen breakage syndrome.
abstract: Nijmegen breakage syndrome (NBS) is a rare autosomal recessive disorder characterized by microcephaly, immunodeficiency, and predisposition to hematopoietic malignancy. The clinical and cellular phenotypes of NBS substantially overlap those of ataxia-telangiectasia (A-T). NBS is caused by mutation of the NBS1 gene, which encodes a member of the Mre11 complex, a trimeric protein complex also containing Mre11 and Rad50. Several lines of evidence indicate that the ataxia-telangiectasia mutated (ATM) kinase and the Mre11 complex functionally interact. Both NBS and A-T cells exhibit ionizing radiation (IR) sensitivity and defects in the intra S phase checkpoint, resulting in radioresistant DNA synthesis (RDS)-the failure to suppress DNA replication origin firing after IR exposure. NBS1 is phosphorylated by ATM in response to IR, and this event is required for activation of the intra S phase checkpoint (the RDS checkpoint). We derived a murine model of NBS, the Nbs1(DeltaB/DeltaB) mouse. Nbs1(DeltaB/DeltaB) cells are phenotypically identical to those established from NBS patients. The Nbs1(DeltaB) allele was synthetically lethal with ATM deficiency. We propose that the ATM-Mre11 complex DNA damage response pathway is essential and that ATM or the Mre11 complex serves as a nexus to additional components of the pathway.
authors.affiliation: Laboratory of Genetics, University of Wisconsin Medical School, Madison, WI, USA.
authors.forename: Bret R
authors.initials: BR
authors.lastname: Williams
authors.forename: Olga K
authors.initials: OK
authors.lastname: Mirzoeva
authors.forename: William F
authors.initials: WF
authors.lastname: Morgan
authors.forename: Junyu
authors.initials: J
authors.lastname: Lin
authors.forename: Wesley
authors.initials: W
authors.lastname: Dunnick
authors.forename: John H J
authors.initials: JH
authors.lastname: Petrini
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D015139:Blotting, Southern; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D019457:Chromosome Breakage; D004249:DNA Damage; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004843:Epistasis, Genetic; D005347:Fibroblasts; D017353:Gene Deletion; D005804:Genes, Lethal / Q000235:genetics; D006801:Humans; D000076228:MRE11 Homologue Protein; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013577:Syndrome; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C121766:MRE11 protein, human; C512689:Mre11a protein, mouse; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D000076228:MRE11 Homologue Protein; D045643:DNA Repair Enzymes