title: Nuclear export of NBN is required for normal cellular responses to radiation.
abstract: Nijmegen breakage syndrome arises from hypomorphic mutations in the NBN gene encoding nibrin, a component of the MRE11/RAD50/nibrin (MRN) complex. In mammalian cells, the MRN complex localizes to the nucleus, where it plays multiple roles in the cellular response to DNA double-strand breaks. In the current study, sequences in mouse nibrin required to direct the nuclear localization of the MRN complex were identified by site-specific mutagenesis. Unexpectedly, nibrin was found to contain both nuclear localizing signal (NLS) sequences and a nuclear export signal (NES) sequence whose functions were confirmed by mutagenesis. Both nuclear import and export sequences were active in vivo. Disruption of either the NLS or NES sequences of nibrin significantly altered the cellular distribution of nibrin and Mre11 and impaired survival after exposure to ionizing radiation. Mutation of the NES sequence in nibrin slowed the turnover of phosphorylated nibrin after irradiation, indicating that nuclear export of nibrin may function, in part, to downregulate posttranslationally modified MRN complex components after DNA damage responses are complete.
authors.affiliation: Molecular Genetics Program, Benaroya Research Institute, Seattle, Washington 98101-27951, USA.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Vissinga
authors.forename: Tiong C
authors.initials: TC
authors.lastname: Yeo
authors.forename: Sarah
authors.initials: S
authors.lastname: Warren
authors.forename: James V
authors.initials: JV
authors.lastname: Brawley
authors.forename: Jennifer
authors.initials: J
authors.lastname: Phillips
authors.forename: Karen
authors.initials: K
authors.lastname: Cerosaletti
authors.forename: Patrick
authors.initials: P
authors.lastname: Concannon
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000528:radiation effects; D000595:Amino Acid Sequence; D000818:Animals; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism* / Q000528:radiation effects*; D002470:Cell Survival / Q000528:radiation effects; D002999:Clone Cells; D017124:Conserved Sequence; D045643:DNA Repair Enzymes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D000076228:MRE11 Homologue Protein; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D041681:NIH 3T3 Cells; D049790:Nuclear Export Signals; D019913:Nuclear Localization Signals / Q000737:chemistry; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D010768:Phosphoserine / Q000378:metabolism; D021381:Protein Transport / Q000528:radiation effects; D011839:Radiation, Ionizing; D015398:Signal Transduction / Q000528:radiation effects; D013347:Subcellular Fractions / Q000378:metabolism / Q000528:radiation effects; D013997:Time Factors
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C512689:Mre11a protein, mouse; C466108:Nijmegen breakage syndrome 1 protein, mouse; D049790:Nuclear Export Signals; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D010768:Phosphoserine; D000076228:MRE11 Homologue Protein; D045643:DNA Repair Enzymes