title: Functional interaction of H2AX, NBS1, and p53 in ATM-dependent DNA damage responses and tumor suppression.
abstract: Ataxia-telangiectasia (A-T) mutated (ATM) kinase signals all three cell cycle checkpoints after DNA double-stranded break (DSB) damage. H2AX, NBS1, and p53 are substrates of ATM kinase and are involved in ATM-dependent DNA damage responses. We show here that H2AX is dispensable for the activation of ATM and p53 responses after DNA DSB damage. Therefore, H2AX functions primarily as a downstream mediator of ATM functions in the parallel pathway of p53. NBS1 appears to function both as an activator of ATM and as an adapter to mediate ATM activities after DNA DSB damage. Phosphorylation of ATM and H2AX induced by DNA DSB damage is normal in NBS1 mutant/mutant (NBS1m/m) mice that express an N-terminally truncated NBS1 at lower levels. Therefore, the pleiotropic A-T-related systemic and cellular defects observed in NBS1m/m mice are due to the disruption of the adapter function of NBS1 in mediating ATM activities. While H2AX is required for the irradiation-induced focus formation of NBS1, our findings indicate that NBS1 and H2AX have distinct roles in DNA damage responses. ATM-dependent phosphorylation of p53 and p53 responses are largely normal in NBS1m/m mice after DNA DSB damage, and p53 deficiency greatly facilitates tumorigenesis in NBS1m/m mice. Therefore, NBS1, H2AX, and p53 play synergistic roles in ATM-dependent DNA damage responses and tumor suppression.
authors.affiliation: Division of Biological Sciences, University of California, San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0322, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Kang
authors.forename: David
authors.initials: D
authors.lastname: Ferguson
authors.forename: Hoseok
authors.initials: H
authors.lastname: Song
authors.forename: Craig
authors.initials: C
authors.lastname: Bassing
authors.forename: Mark
authors.initials: M
authors.lastname: Eckersdorff
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
authors.forename: Yang
authors.initials: Y
authors.lastname: Xu
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology / Q000528:radiation effects; D016147:Genes, Tumor Suppressor; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007621:Karyotyping; D008223:Lymphoma / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011839:Radiation, Ionizing; D012694:Serine / Q000378:metabolism; D014158:Transcription, Genetic; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D064447:Checkpoint Kinase 2; D004268:DNA-Binding Proteins; D006657:Histones; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D012694:Serine; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C466108:Nijmegen breakage syndrome 1 protein, mouse; C576324:ATM protein, human; C576325:Atm protein, mouse; C578634:CHEK2 protein, human; C578633:Chek2 protein, mouse; C475961:gamma-H2AX protein, mouse