title: The MRX Complex Ensures NHEJ Fidelity through Multiple Pathways Including Xrs2-FHA-Dependent Tel1 Activation.
abstract: Because DNA double-strand breaks (DSBs) are one of the most cytotoxic DNA lesions and often cause genomic instability, precise repair of DSBs is vital for the maintenance of genomic stability. Xrs2/Nbs1 is a multi-functional regulatory subunit of the Mre11-Rad50-Xrs2/Nbs1 (MRX/N) complex, and its function is critical for the primary step of DSB repair, whether by homologous recombination (HR) or non-homologous end joining. In human NBS1, mutations result truncation of the N-terminus region, which contains a forkhead-associated (FHA) domain, cause Nijmegen breakage syndrome. Here we show that the Xrs2 FHA domain of budding yeast is required both to suppress the imprecise repair of DSBs and to promote the robust activation of Tel1 in the DNA damage response pathway. The role of the Xrs2 FHA domain in Tel1 activation was independent of the Tel1-binding activity of the Xrs2 C terminus, which mediates Tel1 recruitment to DSB ends. Both the Xrs2 FHA domain and Tel1 were required for the timely removal of the Ku complex from DSB ends, which correlates with a reduced frequency of imprecise end-joining. Thus, the Xrs2 FHA domain and Tel1 kinase work in a coordinated manner to maintain DSB repair fidelity.
authors.affiliation: Department of Integrated Protein Functions, Institute for Protein Research, Osaka University, Suita, Osaka, Japan.|Department of Biological Science, Graduate School of Science, Osaka University, Suita, Osaka, Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Iwasaki
authors.affiliation: Department of Integrated Protein Functions, Institute for Protein Research, Osaka University, Suita, Osaka, Japan.
authors.forename: Kayoko
authors.initials: K
authors.lastname: Hayashihara
authors.affiliation: Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shima
authors.affiliation: Department of Integrated Protein Functions, Institute for Protein Research, Osaka University, Suita, Osaka, Japan.|Department of Biological Science, Graduate School of Science, Osaka University, Suita, Osaka, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Higashide
authors.affiliation: Department of Integrated Protein Functions, Institute for Protein Research, Osaka University, Suita, Osaka, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Terasawa
authors.affiliation: Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Gasser
authors.affiliation: Department of Integrated Protein Functions, Institute for Protein Research, Osaka University, Suita, Osaka, Japan.|Department of Biological Science, Graduate School of Science, Osaka University, Suita, Osaka, Japan.|Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Shinohara
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage / Q000235:genetics; D059766:DNA End-Joining Repair / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D004706:Endodeoxyribonucleases / Q000235:genetics; D005090:Exodeoxyribonucleases / Q000235:genetics; D059765:Homologous Recombination / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D049932:Nijmegen Breakage Syndrome / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins; C086930:RAD50 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; C086929:XRS2 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; C513623:TEL1 protein, S cerevisiae; D004706:Endodeoxyribonucleases; D005090:Exodeoxyribonucleases; C094191:MRE11 protein, S cerevisiae