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Identification and Characterization of a Human DNA Glycosylase for Repair of Modified Bases in Oxidatively Damaged DNA

Published

Author(s)

T. K. Hazra, T. Izumi, I Boldough, B Imhoff, Y W. Kow, Pawel Jaruga, Miral M. Dizdar, Somenath Mitra

Abstract

8-oxoguanine (8-oxoG), ring-opened purines (formamidopyrimidines or Fapys), and other oxidized DNA base lesions generated by reactive oxygen species, are often mutagenic and toxic, and have been implicated in the etiology of many diseases including cancer, and in aging. Repair of these lesions in all organisms occurs primarily via the DNA base excision repair pathway, initiated with their excision by DNA glycosylase/AP lyases, which are of two classes. One class utilizes an internal Lys residue as the active site nucleophile, and includes Escherichia coli Nth and both known mammalian DNA glycosylase/AP lyases, namely, OGG1 and NTH1. E. coli MutM and its paralog Nei, which comprise the second class, utilize N-terminal Pro as the active site. Here we report for the first time two orthologs of E. coli MutM/Nei in the human genomic database, and characterize one of their products. Based on the substrate preference, we have named it NEH1 (Nei homolog). The 44 kDa wild-type recombinant NEH1, purified to homogeneity from E. coli, excises Fapys from damaged DNA, and oxidized pyrimidines and 8-oxoG from oligodeoxynucleotides. Inactivation of the enzyme due to deletion of N-terminal Pro or Histag fusion at the N terminus supports the role of N-terminal Pro as its active site. The tissue-specific levels of NEH1 and OGG1mRNAs are distinct, and S phase-specific increase in NEH1 at both RNA and protein levels suggests that NEH1 is involved in replication-associated repair of oxidized bases.
Citation
Proceedings of the National Academy of Sciences of the United States of America
Volume
99
Issue
6

Keywords

8-oxoguanine, DNA glycosylases, DNA repair, formamidopyrimidines, mutagenesis, oxidative DNA damage

Citation

Hazra, T. , Izumi, T. , Boldough, I. , Imhoff, B. , Kow, Y. , Jaruga, P. , Dizdar, M. and Mitra, S. (2002), Identification and Characterization of a Human DNA Glycosylase for Repair of Modified Bases in Oxidatively Damaged DNA, Proceedings of the National Academy of Sciences of the United States of America (Accessed April 16, 2024)
Created March 18, 2002, Updated October 12, 2021