title: Multiple DNA glycosylases for repair of 8-oxoguanine and their potential in vivo functions.
abstract: 8-Oxoguanine (8-oxoG) is a critical mutagenic lesion because of its propensity to mispair with A during DNA replication. All organisms, from bacteria to mammals, express at least two types of 8-oxoguanine-DNA glycosylase (OGG) for repair of 8-oxoG. The major enzyme class (OGG1), first identified in Escherichia coli as MutM (Fpg), and later in yeast and humans, excises 8-oxoG when paired with C, T, and G but rarely with A. In contrast, a distinct and less abundant OGG, OGG2, prefers 8-oxoG when paired with G and A as a substrate, and has been characterized in yeast and human cells. Recently, OGG2 activity was detected in E. coli which was subsequently identified to be Nei (Endo VIII). In view of the ubiquity of OGG2, we have proposed a model named "bipartite antimutagenic processing of 8-oxoguanine" and is an extension of the original "GO model." The GO model explains the presence of OGG1 (MutM) that excises 8-oxoG from nonreplicated DNA. If 8-oxoG mispairs with A during replication, MutY excises A and provides an opportunity for insertion of C opposite 8-oxoG during subsequent repair replication. Our model postulates that whereas OGG1 (MutM) is responsible for global repair of 8-oxoG in the nonreplicating genome, OGG2 (Nei) repairs 8-oxoG in nascent or transcriptionally active DNA. Interestingly, we observed that MutY and MutM reciprocally inhibited each other's catalytic activity but observed no mutual interference between Nei and MutY. This suggests that the recognition sites on the same substrate for Nei and MutY are nonoverlapping. Human OGG1 is distinct from other oxidized base-specific DNA glycosylases because of its extremely low turnover, weak AP lyase activity, and nonproductive affinity for the abasic (AP) site, its first reaction product. OGG1 is activated nearly 5-fold in the presence of AP-endonuclease (APE) as a result of its displacement by the latter. These results support the "handoff" mechanism of BER in which the enzymatic steps are coordinated as a result of displacement of the DNA glycosylase by APE, the next enzyme in the pathway. The physiological significance of multiple OGGs and their in vivo reaction mechanisms remain to be elucidated by further studies.
authors.affiliation: Sealy Center for Molecular Science, Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, Texas 77555, USA.
authors.forename: T K
authors.initials: TK
authors.lastname: Hazra
authors.forename: J W
authors.initials: JW
authors.lastname: Hill
authors.forename: T
authors.initials: T
authors.lastname: Izumi
authors.forename: S
authors.initials: S
authors.lastname: Mitra
mesh_terms: D001426:Bacterial Proteins / Q000502:physiology; D019757:Carbon-Oxygen Lyases / Q000502:physiology; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D045647:DNA Glycosylases; D011088:DNA Ligases / Q000145:classification / Q000502:physiology*; D004260:DNA Repair; D004261:DNA Replication; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D043382:DNA-Formamidopyrimidine Glycosylase; D043224:Deoxyribonuclease (Pyrimidine Dimer); D043223:Deoxyribonuclease IV (Phage T4-Induced); D004706:Endodeoxyribonucleases / Q000502:physiology; D029968:Escherichia coli Proteins; D005656:Fungal Proteins / Q000502:physiology; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism*; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D009699:N-Glycosyl Hydrolases / Q000502:physiology; D013379:Substrate Specificity; D014158:Transcription, Genetic
chemical_list: D001426:Bacterial Proteins; D029968:Escherichia coli Proteins; D005656:Fungal Proteins; C024829:8-hydroxyguanine; D006147:Guanine; D004247:DNA; D004706:Endodeoxyribonucleases; D043223:Deoxyribonuclease IV (Phage T4-Induced); C468972:endonuclease IV, E coli; D043224:Deoxyribonuclease (Pyrimidine Dimer); D045647:DNA Glycosylases; D009699:N-Glycosyl Hydrolases; C061738:mutY adenine glycosylase; D043382:DNA-Formamidopyrimidine Glycosylase; C468610:DNA-formamidopyrimidine glycosylase, E coli; D019757:Carbon-Oxygen Lyases; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D011088:DNA Ligases