title: An Approach to Elucidate NBS1 Function in DNA Repair Using Frequent Nonsynonymous Polymorphism in Wild Medaka (Oryzias latipes) Populations.
abstract: Nbs1 is one of the genes responsible for Nijmegen breakage syndrome, which is marked with high radiosensitivity. In human NBS1 (hNBS1), Q185E polymorphism is known as the factor to cancer risks, although its DSB repair defect has not been addressed. Here we investigated the genetic variations in medaka (Oryzias latipes) wild populations, and found 40 nonsynonymous single nucleotide polymorphisms (SNPs) in medaka nbs1 (olnbs1) gene within 5 inbred strains. A mutation to histidine in Q170 residue in olNbs1, which corresponds to Q185 residue of hNBS1, was widely distributed in the closed colonies derived from the eastern Korean population of medaka. Overexpression of H170 type olNbs1 in medaka cultured cell lines resulted in the increased accumulation of olNbs1 at laser-induced DSB sites. Autophosphorylation of DNA-dependent protein kinase at T2609 was suppressed after the γ-ray irradiation, which was followed by prolonged formation of γ-H2AX foci and delayed DSB repair. These findings suggested that the nonsynonymous SNP (Q170H) in olnbs1, which induced DSB repair defects, is specifically distributed in the eastern Korean population of medaka. Furthermore, examination using the variation within wild populations might provide a novel method to characterize a driving force to spread the disease risk alleles.
authors.affiliation: Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan.
authors.forename: Kento
authors.initials: K
authors.lastname: Igarashi
authors.affiliation: Department of Genome Repair Dynamics, Radiation Biology Center, Kyoto University, Kyoto, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Kobayashi
authors.affiliation: Department of Anatomy, Kitasato University School of Medicine, Sagamihara, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Katsumura
authors.affiliation: Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Urushihara
authors.affiliation: Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan.
authors.forename: Kyohei
authors.initials: K
authors.lastname: Hida
authors.affiliation: Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Watanabe-Asaka
authors.affiliation: Department of Anatomy, Kitasato University School of Medicine, Sagamihara, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Oota
authors.affiliation: Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Oda
authors.affiliation: Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan.
authors.forename: Hiroshi
authors.identifier: http://orcid.org/0000-0003-0167-3816
authors.initials: H
authors.lastname: Mitani
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000835:Animals, Wild; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology*; D051747:DNA-Activated Protein Kinase / Q000378:metabolism; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000737:chemistry / Q000502:physiology*; D009990:Oryzias / Q000235:genetics*; D010766:Phosphorylation; D011110:Polymorphism, Genetic; D017386:Sequence Homology, Amino Acid
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D051747:DNA-Activated Protein Kinase