title: Targeted disruption of NBS1 reveals its roles in mouse development and DNA repair.
abstract: Nijmegen breakage syndrome (NBS) is an autosomal recessive hereditary disease that shares some common defects with ataxia-telangiectasia. The gene product mutated in NBS, named NBS1, is a component of the Mre11 complex that is involved in DNA strand-break repair. To elucidate the physiological roles of NBS1, we disrupted the N-terminal exons of the NBS1 gene in mice. NBS1(m/m) mice are viable, growth retarded and hypersensitive to ionizing radiation (IR). NBS1(m/m) mice exhibit multiple lymphoid developmental defects, and rapidly develop thymic lymphoma. In addition, female NBS1(m/m) mice are sterile due to oogenesis failure. NBS1(m/m) cells are impaired in cellular responses to IR and defective in cellular proliferation. Most systematic and cellular defects identified in NBS1(m/m) mice recapitulate those in NBS patients, and are essentially identical to those observed in Atm(-/-) mice. In contrast to Atm(-/-) mice, spermatogenesis is normal in NBS1(m/m) mice, indicating that distinct roles of ATM have differential requirement for NBS1 activity. Thus, NBS1 and ATM have overlapping and distinct functions in animal development and DNA repair.
authors.affiliation: Section of Molecular Biology, Division of Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Kang
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000818:Animals; D001260:Ataxia Telangiectasia / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D002455:Cell Division; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004260:DNA Repair; D004268:DNA-Binding Proteins; D005260:Female; D016195:G2 Phase; D005720:Gamma Rays; D018390:Gene Targeting; D006128:Growth; D007153:Immunologic Deficiency Syndromes; D008221:Lymphoid Tissue / Q000254:growth & development; D008223:Lymphoma / Q000209:etiology / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins; D009865:Oocytes / Q000166:cytology / Q000502:physiology; D009866:Oogenesis / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology; D011836:Radiation Tolerance / Q000235:genetics; D013091:Spermatogenesis / Q000502:physiology; D013094:Spermatozoa / Q000166:cytology / Q000502:physiology; D013953:Thymus Neoplasms / Q000209:etiology / Q000235:genetics; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D004247:DNA; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases