title: Nijmegen breakage syndrome gene, NBS1, and molecular links to factors for genome stability.
abstract: DNA double-strand breaks represent the most potentially serious damage to a genome and hence, at least two pathways of DNA repair have evolved; namely, homologous recombination repair and non-homologous end joining. Defects in both rejoining processes result in genomic instability including chromosome rearrangements, LOH and gene mutations, which may lead to development of malignancies. Nijmegen breakage syndrome is a recessive genetic disorder, characterized by elevated sensitivity to ionizing radiation that induces double-strand breaks, and high frequency of malignancies. NBS1, the product of the gene underlying the disease, forms a multimeric complex with hMRE11/hRAD50 nuclease and recruits them to the vicinity of sites of DNA damage by direct binding to phosphorylated histone H2AX. The combination of the highly-conserved NBS1 forkhead associated domain and BRCA1 C-terminus domain has a crucial role for recognition of damaged sites. Thereafter, the NBS1-complex proceeds to rejoin double-strand breaks predominantly by homologous recombination repair in vertebrates. This process collaborates with cell-cycle checkpoints at S and G2 phase to facilitate DNA repair. NBS1 is also associated with telomere maintenance and DNA replication. Based on recent knowledge regarding NBS1, we propose here a two-step binding mechanism for damage recognition by repair proteins, and describe the molecular links to factors for genome stability.
authors.affiliation: Department of Environmental Sciences, Ibaraki University, Mito, Ibaraki 310-8512, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tauchi
authors.forename: Shinya
authors.initials: S
authors.lastname: Matsuura
authors.forename: Junya
authors.initials: J
authors.lastname: Kobayashi
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sakamoto
authors.forename: Kenshi
authors.initials: K
authors.lastname: Komatsu
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D019457:Chromosome Breakage; D025063:Chromosome Disorders / Q000209:etiology* / Q000235:genetics; D004260:DNA Repair / Q000502:physiology; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005656:Fungal Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015894:Genome, Human; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000076228:MRE11 Homologue Protein; D051379:Mice; D009369:Neoplasms / Q000235:genetics; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation; D011995:Recombination, Genetic; D029701:Saccharomyces cerevisiae Proteins; D016615:Telomere / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C468783:H2AX protein, human; D006657:Histones; C121766:MRE11 protein, human; C512689:Mre11a protein, mouse; C112156:NBN protein, human; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; C086930:RAD50 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D000076228:MRE11 Homologue Protein; D045643:DNA Repair Enzymes