Abstract
8-Oxoguanine (8-oxoG), induced by reactive oxygen species (ROS) and ionizing radiation, is arguably the most important mutagenic lesion in DNA. This oxidized base, because of its mispairing with A, induces GC→TA transversion mutations often observed spontaneously in tumor cells. The human cDNA encoding the repair enzyme 8-oxoG-DNA glycosylase (OGG-1) has recently been cloned, however, its activity was never detected in cells. Here we show that the apparent lack of this activity could be due to the presence of an 8-oxoG-specific DNA binding protein. Moreover, we demonstrate the presence of two antigenically distinct OGG activities with an identical reaction mechanism in human cell (HeLa) extracts. The 38 kDa OGG-1, identical to the cloned enzyme, cleaves 8-oxoG when paired with cytosine, thymine and guanine but not adenine in DNA. In contrast, the newly discovered 36 kDa OGG-2 prefers 8-oxoG paired with G and A. We propose that OGG-1 and OGG-2 have distinct antimutagenic functions in vivo. OGG-1 prevents mutation by removing 8-oxoG formed in DNA in situ and paired with C, while OGG-2 removes 8-oxoG that is incorporated opposite A in DNA from ROS-induced 8-oxodGTP. We predict that OGG-2 specifically removes such 8-oxoG residues only from the nascent strand, possibly by utilizing the same mechanism as the DNA mismatch repair pathway.
Original language | English |
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Pages (from-to) | 5116-5122 |
Number of pages | 7 |
Journal | Nucleic Acids Research |
Volume | 26 |
Issue number | 22 |
DOIs | |
State | Published - Nov 15 1998 |
Bibliographical note
Funding Information:We would like to thank Drs Y. W. Kow and B. Van Houten for gifts of enzymes and for scientific discussions and Dr M. R. Kelley for providing unpublished information. We thank Dr A. Kurosky and Mr S. Serabyn for synthesis and purification of a 19mer peptide. Ms Julie Lock provided expert technical assistance. Dr D. Konkel’s editing of the manuscript and Ms Wanda Smith’s secretarial help are also gratefully acknowledged. This study was supported by US Public Health Service Grants CA53791 and ES08457, NIEHS Center Grant ES06676 and NIA Program Project Grants AG 10514 (to S.M.) and HL53585 (to R.A.F.).
ASJC Scopus subject areas
- Genetics