title: Regulation of base excision repair: Ntg1 nuclear and mitochondrial dynamic localization in response to genotoxic stress.
abstract: Numerous human pathologies result from unrepaired oxidative DNA damage. Base excision repair (BER) is responsible for the repair of oxidative DNA damage that occurs in both nuclei and mitochondria. Despite the importance of BER in maintaining genomic stability, knowledge concerning the regulation of this evolutionarily conserved repair pathway is almost nonexistent. The Saccharomyces cerevisiae BER protein, Ntg1, relocalizes to organelles containing elevated oxidative DNA damage, indicating a novel mechanism of regulation for BER. We propose that dynamic localization of BER proteins is modulated by constituents of stress response pathways. In an effort to mechanistically define these regulatory components, the elements necessary for nuclear and mitochondrial localization of Ntg1 were identified, including a bipartite classical nuclear localization signal, a mitochondrial matrix targeting sequence and the classical nuclear protein import machinery. Our results define a major regulatory system for BER which when compromised, confers a mutator phenotype and sensitizes cells to the cytotoxic effects of DNA damage.
authors.affiliation: Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA.
authors.forename: Dan B
authors.initials: DB
authors.lastname: Swartzlander
authors.forename: Lyra M
authors.initials: LM
authors.lastname: Griffiths
authors.forename: Joan
authors.initials: J
authors.lastname: Lee
authors.forename: Natalya P
authors.initials: NP
authors.lastname: Degtyareva
authors.forename: Paul W
authors.initials: PW
authors.lastname: Doetsch
authors.forename: Anita H
authors.initials: AH
authors.lastname: Corbett
mesh_terms: D021581:Active Transport, Cell Nucleus; D019943:Amino Acid Substitution; D002467:Cell Nucleus / Q000201:enzymology*; D004249:DNA Damage; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism; D008928:Mitochondria / Q000201:enzymology*; D019913:Nuclear Localization Signals; D018384:Oxidative Stress; D021382:Protein Sorting Signals; D029701:Saccharomyces cerevisiae Proteins / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism
chemical_list: D019913:Nuclear Localization Signals; D021382:Protein Sorting Signals; D029701:Saccharomyces cerevisiae Proteins; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; C101825:NTG1 protein, S cerevisiae