Oxidative genome damage and its repair: implications in aging and neurodegenerative diseases.
Reactive oxygen species (ROS), generated endogenously during respiration or exogenously by genotoxic agents, induce oxidized bases and single-strand breaks (SSBs) in DNA that are repaired via the base excision/SSB repair (BER/SSBR) pathway in both the nucleus and mitochondria. Tightly regulated BER/SSBR with multiple sub-pathways is highly complex, and is linked to the replication and transcription. The repair-initiating DNA glycosylases (DGs) or AP-endonuclease (APE1) control the sub-pathway by stably interacting with downstream proteins usually via their common interacting domain (CID). A nonconserved CID with disordered structure usually located at one of the termini includes the sequences for covalent modifications and/or organelle targeting. While the DGs are individually dispensable, the SSBR-initiating APE1 and polynucleotide kinase 3' phosphatase (PNKP) are essential. BER/SSBR of mammalian nuclear and mitochondrial genomes share the same early enzymes. Accumulation of oxidative damage in nuclear and mitochondrial genomes has been implicated in aging and various neurological disorders. While defects in BER/SSBR proteins have been linked to hereditary neurodegenerative diseases, our recent studies implicated transition metal-induced inhibition of NEIL family DGs in sporadic diseases. This review focuses on the recent advances in repair of oxidatively damages in mammalian genomes and their linkage to aging and neurological disorders.
Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555-1079, USA.
Muralidhar L
ML
Hegde
Anil K
AK
Mantha
Tapas K
TK
Hazra
Kishor K
KK
Bhakat
Sankar
S
Mitra
Bartosz
B
Szczesny
D000367:Age Factors; D000375:Aging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D053904:DNA Breaks, Single-Stranded; D004249:DNA Damage; D045647:DNA Glycosylases / Q000378:metabolism; D004260:DNA Repair; D004272:DNA, Mitochondrial / Q000378:metabolism; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000378:metabolism; D006801:Humans; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*
D004272:DNA, Mitochondrial; D017382:Reactive Oxygen Species; D017853:Phosphotransferases (Alcohol Group Acceptor); D045647:DNA Glycosylases; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase