Repair of Oxidative Damage to Nuclear and Mitochondrial DNA in Mammalian Cells

Abstract

Reactive oxygen species (ROS) 1The abbreviations used are: ROS, reactive oxygen species; BER, base excision repair; NER, nucleotide excision repair; AD, Alzheimer's disease; endo, endonuclease; TCR, transcription-coupled repair; 8-oxoG, 8-hydroxyguanine; 8-oxodG, 8-hydroxydeoxyguanine; TG, thymine glycol; AP, apurinic/apyrimidinc; GSR, gene-specific repair assay; XP, xeroderma pigmentosum; CS, Cockayne's syndrome; FapyG, 2,6-diamino-4hydroxyl-5-methylformamidopyrimidine. 1The abbreviations used are: ROS, reactive oxygen species; BER, base excision repair; NER, nucleotide excision repair; AD, Alzheimer's disease; endo, endonuclease; TCR, transcription-coupled repair; 8-oxoG, 8-hydroxyguanine; 8-oxodG, 8-hydroxydeoxyguanine; TG, thymine glycol; AP, apurinic/apyrimidinc; GSR, gene-specific repair assay; XP, xeroderma pigmentosum; CS, Cockayne's syndrome; FapyG, 2,6-diamino-4hydroxyl-5-methylformamidopyrimidine. are generated in cells as a by-product of cellular metabolism. ROS react with proteins, lipids, and DNA. DNA base modifications, abasic sites, deoxyribose damage, and single and double strand breaks are all induced following various forms of oxidative stress. This review will focus on DNA repair of oxidative lesions by base excision repair (BER) and nucleotide excision repair (NER). We will focus on the mammalian BER enzymes that have recently been cloned and characterized. Mitochondrial DNA repair mechanisms for oxidative damage will also be discussed. Although sugar damage and double strand breaks are critical lesions induced by ionizing radiation and bleomycin, repair of these lesions will not be discussed here (see Refs. 1Weaver D.T. Crit. Rev. Eukaryotic Gene Expression. 1996; 6: 345-375Crossref PubMed Scopus (44) Google Scholar, 2Lieber M.R. Grawunder U. Wu X. Yaneva M. Curr. Opin. Genet. Dev. 1997; 7: 99-104Crossref PubMed Scopus (127) Google Scholar, 3Povirk L.F. Mutat. Res. 1996; 355: 71-89Crossref PubMed Scopus (333) Google Scholar for recent reviews).Oxidative DNA Damage and Its ConsequencesThe endogenous attack on DNA by ROS species generates a low steady-state level of DNA adducts that have been detected in the DNA from human cells (4Dizdaroglu M. Halliwell B. Aruoma O.I. DNA and Free Radicals. Ellis Horwood, Ltd., London, United Kingdom1993: 18-39Google Scholar). Some of these base modifications are shown in Fig. 1. There are many more, and it is possible that the full spectrum of oxidative lesions in endogenous mammalian DNA exceeds 100 different types, of which 8-hydroxyguanine (8-oxoG) is one of the most abundant (5Ames B.N. Free Radical Res. Commun. 1989; 7: 121-128Crossref PubMed Scopus (627) Google Scholar).Oxidative DNA damage is thought to contribute to carcinogenesis, aging, and neurological degeneration (for reviews, see Refs. 5Ames B.N. Free Radical Res. Commun. 1989; 7: 121-128Crossref PubMed Scopus (627) Google Scholar and 6Wiseman H. Halliwell B. Biochem. J. 1996; 313: 17-29Crossref PubMed Scopus (1943) Google Scholar). Studies have shown that oxidative DNA damage accumulates in cancerous tissue. For example, higher levels of oxidative base damage were observed in lung cancer tissue compared with surrounding normal tissue (7Olinski R. Zastawny T. Budzbin J. Skokowski J. Zegarski W. Dizdaroglu M. FEBS Lett. 1992; 309: 193-198Crossref PubMed Scopus (243) Google Scholar). Another study reported a 9-fold increase in 8-oxoG, 8-hydroxyadenine, and 2,6-diamino-4-hydroxy-5-formamidopyrimidine in DNA from breast cancer tissue compared with normal tissue (8Malins D.C. Haimanot R. Cancer Res. 1991; 51: 5430-5432PubMed Google Scholar). Further, the cumulative risk of cancer increases dramatically with age in humans (9Ames B.N. Mutat. Res. 1989; 214: 41-46Crossref PubMed Scopus (290) Google Scholar), and cancer can in general terms be regarded as a degenerative disease of old age. There is evidence for the accumulation of oxidative DNA damage with age based on studies mainly measuring the increase in 8-oxoG (10Sohal R.S. Ku H.H. Agarwal H. Dev. PubMed Scopus Google Scholar). Alzheimer's disease studies have shown accumulation of oxidative DNA damage in the and a recent study in cells from Alzheimer's disease a in the of damage by U. 1996; PubMed Scopus Google Scholar). of were by the of and it that oxidative DNA damage and for the in cells U. 1996; PubMed Scopus Google Scholar). cells also to ionizing radiation and and it is possible that lesions by these as oxidative modifications, DNA strand breaks are not in cells Mutat. Res. PubMed Scopus Google have been used to cells to oxidative damage, all to endogenous (4Dizdaroglu M. Halliwell B. Aruoma O.I. DNA and Free Radicals. Ellis Horwood, Ltd., London, United Kingdom1993: 18-39Google Scholar, 6Wiseman H. Halliwell B. Biochem. J. 1996; 313: 17-29Crossref PubMed Scopus (1943) Google Scholar). Some studies have used which generates a spectrum of radiation also generates a spectrum of lesions base damage and single and double strand breaks in