Dynamic compartmentalization of base excision repair proteins in response to nuclear and mitochondrial oxidative stress.
DNAs harbored in both nuclei and mitochondria of eukaryotic cells are subject to continuous oxidative damage resulting from normal metabolic activities or environmental insults. Oxidative DNA damage is primarily reversed by the base excision repair (BER) pathway, initiated by N-glycosylase apurinic/apyrimidinic (AP) lyase proteins. To execute an appropriate repair response, BER components must be distributed to accommodate levels of genotoxic stress that may vary considerably between nuclei and mitochondria, depending on the growth state and stress environment of the cell. Numerous examples exist where cells respond to signals, resulting in relocalization of proteins involved in key biological transactions. To address whether such dynamic localization contributes to efficient organelle-specific DNA repair, we determined the intracellular localization of the Saccharomyces cerevisiae N-glycosylase/AP lyases, Ntg1 and Ntg2, in response to nuclear and mitochondrial oxidative stress. Fluorescence microscopy revealed that Ntg1 is differentially localized to nuclei and mitochondria, likely in response to the oxidative DNA damage status of the organelle. Sumoylation is associated with targeting of Ntg1 to nuclei containing oxidative DNA damage. These studies demonstrate that trafficking of DNA repair proteins to organelles containing high levels of oxidative DNA damage may be a central point for regulating BER in response to oxidative stress.
Griffiths
Lyra M
LM
Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Swartzlander
Dan
D
Meadows
Kellen L
KL
Wilkinson
Keith D
KD
Corbett
Anita H
AH
Doetsch
Paul W
PW
D000595:Amino Acid Sequence; D000968:Antimycin A / Q000031:analogs & derivatives / Q000494:pharmacology; D002451:Cell Compartmentation / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000737:chemistry / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008741:Methyl Methanesulfonate / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology*; D008954:Models, Biological; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000378:metabolism; D018384:Oxidative Stress; D010100:Oxygen / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D012441:Saccharomyces cerevisiae / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000378:metabolism*; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology
D050505:Mutant Proteins; D029701:Saccharomyces cerevisiae Proteins; D025841:Small Ubiquitin-Related Modifier Proteins; C032456:antimycin; D000968:Antimycin A; D008741:Methyl Methanesulfonate; D006861:Hydrogen Peroxide; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; C101825:NTG1 protein, S cerevisiae; C116827:NTG2 protein, S cerevisiae; D010100:Oxygen