Environmental and endogenous mutagens are the major causes of DNA mutations
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Peer-reviewed scientific literature extensively documents that both environmental exposures and endogenous cellular processes are major sources of DNA damage and mutations.
Most human cancers result from environmental exposures and gene-environment interactions. Diet is an important component of lifestyle and its role in the maintenance of good health and as a determinant of different kind of chronic diseases, including cancer, has been extensively analyzed. Diet can contribute to cancer risk through the consumption of food mutagens, including those generated by cooking. On the other hand, diet that emphasizes the consumption of whole grain foods, legumes, vegetables and fresh fruit and that limit animal fat has been associated with decreased cancer risk. Indeed, a general protective effect against cancers at different sites has been reported for a number of fresh fruit and vegetables. In particular, fresh fruit is a food rich of phytochemicals that can act against reactive oxygen species (ROS) formation and induce the expression of DNA repair systems. Among life-style habits, tobacco cigarette smoking is an established cancer risk factor. In addition to be a relevant source of mutagens, tobacco smoke is also a major source of oxidative stress and ROS, capable to cause oxidative DNA damage. ROS can also induce lipid peroxidation (LPO), whose by-products can lead to endogenous DNA damage formation. MDA is a natural product of LPO, also formed during prostaglandins (PGH2) biosynthesis via cyclooxygenase (COX-1 and COX-2). MDA is an aldehyde capable to interact with cellular constituents including DNA, inducing the formation of M1dG adducts. The re
DNA adducts are a major cause of DNA mutation and DNA mutation-related diseases, but the simultaneous identification of multiple DNA adducts has been a challenge for a decade. An adductome approach using consecutive liquid chromatography and double mass spectrometry after micrococcal nuclease treatment has paved the way to demonstrations of numerous DNA adducts in a single experiment and is expected to contribute to the comprehensive understanding of overall environmental and endogenous exposures to possible mutagens in individuals. In this report, we applied an adductome approach to gastric mucosa samples taken at the time of a gastrectomy for gastric cancer in Lujiang, China, and in Hamamatsu, Japan. Seven lipid peroxidation-related DNA adducts [1,N6-etheno-2'-deoxyadenosine, butanone-etheno-2'-deoxycytidine (BεdC), butanone-etheno-2'-deoxy-5-methylcytidine, butanone-etheno-2'-deoxyadenosine (BεdA), heptanone-etheno-2'-deoxycytidine, heptanone-etheno-2'-deoxyadenosine (HεdA) and heptanone-etheno- 2'-deoxyguanosine] were identified in a total of 22 gastric mucosa samples. The levels of these adducts ranged from 0 to 30,000 per 10(9) bases. Although the presence of Helicobacter pylori DNA in the mucosa was not related to these adducts level, the levels of BεdC, BεdA and HεdA were higher in the Japanese gastric mucosa samples. The profiles of these 7 adduct levels among the 21 cases were capable of discriminating between the possible origins (China or Japan) of the gastric muc
Exposure to environmental mutagens but also cell-endogenous processes can create DNA double-strand breaks (DSBs) in a cell's genome. DSBs need to be repaired accurately and timely to ensure genomic integrity and cell survival. One major DSB repair mechanism, called homologous recombination, relies on the nucleolytic degradation of the 5'-terminated strands in a process termed end resection. Here, we review new insights into end resection with a focus on the mechanistic interplay of the nucleases, helicases, and accessory factors involved.
Oxidative DNA damage is a major cause of mutation and cell death in aerobic organisms. In addition to 8-hydroxyguanine, oxidized DNA pyrimidines play important roles in mutagenesis. Salmonella typhimurium TA1535, widely used in mutagenicity assays, carries a hisG46 missense mutation and efficiently detects mutations at G:C base pairs. To detect oxidative mutagens that selectively modify pyrimidines, we constructed a derivative of strain TA1535, termed YG3206, which lacks the Nei and Nth DNA glycosylases that excise oxidized pyrimidines from DNA. This novel strain easily detected the mutagenicity of L-cysteine, L-penicillamine, dopamine-HCl, and phenazine methosulfate, which are non-mutagenic or only weakly mutagenic in the TA1535 parent strain. A second strain that is equivalent to YG3206 but harbors the plasmid pKM101 which carries mucAB encoding DNA polymerase R1, termed YG3216, was significantly sensitive to phenazine ethosulfate. The compound was not mutagenic in either YG3206 or the Fapy-glycosylase-defective strain YG3001. Potassium bromate and methylene blue plus visible light with metabolic activation induced mutations in YG3001 but not YG3206 or YG3216. The number of spontaneous His+ revertants per plate was 82 ± 16 (YG3206, ΔnthΔnei), 19 ± 4 (YG3001, Δfpg), and 6 ± 2 (TA1535), suggesting a significant contribution to spontaneous mutagenesis by endogenous pyrimidine oxidation. In the absence of exogenous chemical treatment, exposure to fluorescent light enhanced the
Human genome is continuously exposed to exogenous and endogenous genotoxic agents. The most hazardous and ubiquitous exogenous mutagen may be cigarette smoke, which contains more than 4,000 chemicals including about 60 known carcinogens. About 1% of oxygen metabolism leads to production of reactive oxygen species, a major source of endogenous mutagens. These genotoxic agents induce a variety of lesions in DNA, which results in mutations and chromosome aberrations upon replication. If such genetic alterations occurred in the genes involved in cell proliferations and/or maintenance of genome stability, the cells would proceed in multi-steps of carcinogenesis. The goal of environmental mutagenesis and genetic toxicology is to elucidate the mechanistic links between exposure to genotoxic agents and the health consequences, and to prevent the health hazard associated with DNA damage. To this end, we have investigated the mechanisms of mutagenesis induced by environmental chemicals and contributed to establish the paradigm that Y-family DNA polymerases play central roles in mutagenesis via translesion DNA synthesis across damaged bases in DNA. We also developed genotoxicity assays with bacteria and mice to evaluate the potential risk of environmental chemicals. Here, I review the roles of Y-family DNA polymerases in mutagenesis and introduce features of the novel bacterial and rodent genotoxicity assays. Future directions of environmental mutagenesis and carcinogenesis are also dis
Next-generation sequencing (NGS) technology has demonstrated that the cancer genomes are peppered with mutations. Although most somatic tumour mutations are unlikely to have any role in the cancer process per se, the spectra of DNA sequence changes in tumour mutation catalogues have the potential to identify the mutagens, and to reveal the mutagenic processes responsible for human cancer. Very recently, a novel approach for data mining of the vast compilations of tumour NGS data succeeded in separating and precisely defining at least 30 distinct patterns of sequence change hidden in mutation databases. At least half of these mutational signatures can be readily assigned to known human carcinogenic exposures or endogenous mechanisms of mutagenesis. A quantum leap in our knowledge of mutagenesis in human cancers has resulted, stimulating a flurry of research activity. We trace here the major findings leading first to the hypothesis that carcinogenic insults leave characteristic imprints on the DNA sequence of tumours, and culminating in empirical evidence from NGS data that well-defined carcinogen mutational signatures are indeed present in tumour genomic DNA from a variety of cancer types. The notion that tumour DNAs can divulge environmental sources of mutation is now a well-accepted fact. This approach to cancer aetiology has also incriminated various endogenous, enzyme-driven processes that increase the somatic mutation load in sporadic cancers. The tasks now confronting th
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