title: Repair of oxidative DNA damage: mechanisms and functions.
abstract: Cellular genomes suffer extensive damage from exogenous agents and reactive oxygen species formed during normal metabolism. The MutT homologs (MutT/MTH) remove oxidized nucleotide precursors so that they cannot be incorporated into DNA during replication. Among many repair pathways, the base excision repair (BER) pathway is the most important cellular protection mechanism responding to oxidative DNA damage. The 8-oxoG glycosylases (Fpg or MutM/OGG) and the MutY homologs (MutY/MYH) glycosylases along with MutT/MTH protect cells from the mutagenic effects of 8-oxoG, the most stable and deleterious product known caused by oxidative damage to DNA. The key enzymes in the BER process are DNA glycosylases, which remove different damaged bases by cleavage of the N-glycosylic bonds between the bases and the deoxyribose moieties of the nucleotide residues. Biochemical and structural studies have demonstrated the substrate recognition and reaction mechanism of BER enzymes. Cocrystal structures of several glycosylases show that the substrate base flips out of the sharply bent DNA helix and the minor groove is widened to be accessed by the glycosylases. To complete the repair after glycosylase action, the apurinic/apyrimidinic (AP) site is further processed by an incision step, DNA synthesis, an excision step, and DNA ligation through two alternative pathways. The short-patch BER (1-nucleotide patch size) and long-patch BER (2-6-nucleotide patch size) pathways need AP endonuclease to generate a 3' hydroxyl group but require different sets of enzymes for DNA synthesis and ligation. Protein-protein interactions have been reported among the enzymes involved in BER. It is possible that the successive players in the repair pathway are assembled in a complex to perform concerted actions. The BER pathways are proposed to protect cells and organisms from mutagenesis and carcinogenesis.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore 21201, USA. aluchang@umaryland.edu
authors.forename: A L
authors.initials: AL
authors.lastname: Lu
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: Gu
authors.forename: P M
authors.initials: PM
authors.lastname: Wright
authors.forename: D Y
authors.initials: DY
authors.lastname: Chang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D020137:Base Pair Mismatch; D019757:Carbon-Oxygen Lyases / Q000378:metabolism; D004247:DNA; D004249:DNA Damage; D045647:DNA Glycosylases; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D043382:DNA-Formamidopyrimidine Glycosylase; D004926:Escherichia coli / Q000378:metabolism; D029968:Escherichia coli Proteins; D006151:Guanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009699:N-Glycosyl Hydrolases / Q000378:metabolism; D010100:Oxygen / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D011485:Protein Binding; D011755:Pyrophosphatases; D017382:Reactive Oxygen Species
chemical_list: D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D017382:Reactive Oxygen Species; D006151:Guanosine; C046215:8-hydroxyguanosine; D004247:DNA; D010744:Phosphoric Monoester Hydrolases; D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; C061738:mutY adenine glycosylase; D043382:DNA-Formamidopyrimidine Glycosylase; C468610:DNA-formamidopyrimidine glycosylase, E coli; D011755:Pyrophosphatases; C052211:mutT protein, E coli; D019757:Carbon-Oxygen Lyases; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D010100:Oxygen