Pathways for repairing and tolerating the spectrum of oxidative DNA lesions

• Published in: Cancer letters Vol. 327; no. 1-2; pp. 61 - 72
• Main Authors: Berquist, Brian R, Wilson, David M
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier Ireland Ltd 31.12.2012; Elsevier Limited
• Subjects: anemia; Animals; carcinogenesis; Cockayne Syndrome - genetics; Cockayne Syndrome - metabolism; crosslinking; Deoxyribonucleic acid; DNA; DNA Damage; DNA Repair; DNA Replication; DNA-Directed DNA Polymerase - metabolism; DNA-Directed RNA Polymerases - metabolism; Excision repair; exogenous sources; Fanconi Anemia - genetics; Fanconi Anemia - metabolism; Fanconi syndrome; Free radicals; Gene expression; Gene Expression Regulation; Genetic Predisposition to Disease; genome; Genomes; Hematology, Oncology and Palliative Medicine; Hereditary disorder; Heredity; human diseases; Humans; Interstrand crosslink; Kinases; Lipids; Mutagenesis; Oxidative DNA damage; Oxidative Stress; Polymerization; Proteins; reactive oxygen species; Reactive Oxygen Species - metabolism; RNA polymerase; sugars; transcription (genetics); Xeroderma Pigmentosum - genetics; Xeroderma Pigmentosum - metabolism; Excision repair; Hereditary disorder; Interstrand crosslink; Oxidative DNA damage
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2012.02.001

Reactive oxygen species (ROS) arise from both endogenous and exogenous sources. These reactive molecules possess the ability to damage both the DNA nucleobases and the sugar phosphate backbone, leading to a wide spectrum of lesions, including non-bulky (8-oxoguanine and formamidopyrimidine) and bulky (cyclopurine and etheno adducts) base modifications, abasic sites, non-conventional single-strand breaks, protein–DNA adducts, and intra/interstrand DNA crosslinks. Unrepaired oxidative DNA damage can result in bypass mutagenesis during genome copying or gene expression, or blockage of the essential cellular processes of DNA replication or transcription. Such outcomes underlie numerous pathologies, including, but not limited to, carcinogenesis and neurodegeneration, as well as the aging process. Cells have adapted and evolved defense systems against the deleterious effects of ROS, and specifically devote a number of cellular DNA repair and tolerance pathways to combat oxidative DNA damage. Defects in these protective pathways trigger hereditary human diseases that exhibit increased cancer incidence, developmental defects, neurological abnormalities, and/or premature aging. We review herein classic and atypical oxidative DNA lesions, outcomes of encountering these damages during DNA replication and transcription, and the consequences of losing the ability to repair the different forms of oxidative DNA damage. We particularly focus on the hereditary human diseases Xeroderma Pigmentosum, Cockayne Syndrome and Fanconi Anemia, which may involve defects in the efficient repair of oxidative modifications to chromosomal DNA.