Formation and repair of tobacco carcinogen-derived bulky DNA adducts.

Bo Hang

doi:10.4061/2010/709521

Abstract

DNA adducts play a central role in chemical carcinogenesis. The analysis of formation and repair of smoking-related DNA adducts remains particularly challenging as both smokers and nonsmokers exposed to smoke are repetitively under attack from complex mixtures of carcinogens such as polycyclic aromatic hydrocarbons and N-nitrosamines. The bulky DNA adducts, which usually have complex structure, are particularly important because of their biological relevance. Several known cellular DNA repair pathways have been known to operate in human cells on specific types of bulky DNA adducts, for example, nucleotide excision repair, base excision repair, and direct reversal involving O6-alkylguanine DNA alkyltransferase or AlkB homologs. Understanding the mechanisms of adduct formation and repair processes is critical for the assessment of cancer risk resulting from exposure to cigarette smoke, and ultimately for developing strategies of cancer prevention. This paper highlights the recent progress made in the areas concerning formation and repair of bulky DNA adducts in the context of tobacco carcinogen-associated genotoxic and carcinogenic effects.

Highlights

Tobacco was traded from North America to the world about 500 years ago
Similar data were obtained from knockout mice [248], which showed that the Abh2 activity is not sufficient for the removal of spontaneously produced εA adducts in Aag−/− mouse liver, whereas mouse Aag activity is sufficient to repair spontaneously produced εA lesions in Abh2−/− mouse liver. These results suggest that both AAG and ABH2/3 proteins can play a role in the cellular response to the exposure of tobacco carcinogens that generate these ε-adducts
It should be emphasized that most of the repair studies in the past have applied a single compound for modification or exposure, and results from such studies cannot be extrapolated to real exposures

Summary

Introduction

Tobacco was traded from North America to the world about 500 years ago. Since tobacco use by smoking cigarettes, cigars, and pipes, or by chewing, has wreaked havoc on mankind. The understanding of damage recognition and mechanism of repair is important to gain insight into the specific roles of tobacco DNA adducts in the development of cancer and other chronic diseases since, at the end, the overall cellular repair capacity in response to exposure is critically related to the levels of DNA adducts in the genome or mutations in genes. The role of individual variability in repair, for example, polymorphisms in repair genes, has been related to the increased cancer risk in smokers [22, 65, 66] It is the impaired or poor repair of DNA adducts (e.g., those bulky adducts and oxidized bases with cytotoxicity and mutagenicity) that is expected to be most important in the etiology of smoking-related cancer and other disorders. I regret that this review does not permit acknowledgment of the many researchers who made the original findings in these important areas

Formation of Bulky DNA Adducts

Repair of Bulky DNA Adducts

Repair of Specific DNA Adducts by Different Pathways

Findings

From the Known to the Unknown