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1.
Mechanism of arsenic carcinogenesis: an integrated approach 总被引:33,自引:0,他引:33
Rossman TG 《Mutation research》2003,533(1-2):37-65
Epidemiological evidence shows an association between inorganic arsenic in drinking water and increased risk of skin, lung and bladder cancers. The lack of animal models has hindered mechanistic studies of arsenic carcinogenesis in the past, but some promising new models for these cancers are now available. The various forms of arsenic to which humans are exposed, either directly or via metabolism of inorganic arsenic to various methylated forms, further complicate the issue of mechanism, since these compounds can have different effects, both genotoxic and non-genotoxic. This review will try to integrate all of these issues, with a strong bias toward effects that are produced by environmentally relevant arsenic concentrations. 相似文献
2.
Regulation of DNA double-strand break repair pathway choice 总被引:29,自引:0,他引:29
DNA double-strand breaks (DSBs) are critical lesions that can result in cell death or a wide variety of genetic alterations including largeor small-scale deletions, loss of heterozygosity, translocations, and chromosome loss. DSBs are repaired by non-homologous end-joining (NHEJ) and homologous recombination (HR), and defects in these pathways cause genome instability and promote tumorigenesis. DSBs arise from endogenous sources including reactive oxygen species generated during cellular metabolism, collapsed replication forks, and nucleases, and from exogenous sources including ionizing radiation and chemicals that directly or indirectly damage DNA and are commonly used in cancer therapy. The DSB repair pathways appear to compete for DSBs, but the balance between them differs widely among species, between different cell types of a single species, and during different cell cycle phases of a single cell type. Here we review the regulatory factors that regulate DSB repair by NHEJ and HR in yeast and higher eukaryotes. These factors include regulated expression and phosphorylation of repair proteins, chromatin modulation of repair factor accessibility, and the availability of homologous repair templates. While most DSB repair proteins appear to function exclusively in NHEJ or HR, a number of proteins influence both pathways, including the MRE11/RAD50/NBS1(XRS2) complex, BRCA1, histone H2AX, PARP-1, RAD18, DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and ATM. DNA-PKcs plays a role in mammalian NHEJ, but it also influences HR through a complex regulatory network that may involve crosstalk with ATM, and the regulation of at least 12 proteins involved in HR that are phosphorylated by DNA-PKcs and/or ATM. 相似文献
3.
Variation in DNA repair is a factor in cancer susceptibility: a paradigm for the promises and perils of individual and population risk estimation? 总被引:26,自引:0,他引:26
The repair of DNA damage protects the genome of the cell from the insults of cancer causing agents. This was originally demonstrated in individuals with the rare genetic disease, xeroderma pigmentosum, the prototype of cancer genes, and subsequently in the relationship of mismatch repair to colon cancer. Recent studies suggests that individuals with less dramatic reductions in the capacity to repair DNA damage are observed at polymorphic frequency and these individuals have an increased susceptibility to several types of cancer. Screening of individuals for DNA sequence variation in the exons of 9 DNA repair genes has resulted in identification of 15 different polymorphic amino acid substitution variants. Although the studies to relate these variants to reduced DNA repair capacity and cancer status have not been completed, the available information is sufficient to suggest that DNA repair genes should be incorporated into molecular epidemiology and cancer susceptibility studies. The availability of molecular epidemiology data presents exciting opportunities for refinement of risk estimation models and identification of individuals at increased risk of disease, with resultant opportunities for effective surveillance and early intervention and treatment. The opportunities to acquire susceptibility data are associated with possible perils for establishment of regulations for permissible exposures to carcinogenic agents and also stigmatization of ‘at risk’ individuals that may result in decreased access to employment opportunities and health care. 相似文献
4.
单细胞凝胶电泳(single cell gel electrophoresis assay,SCGE)也叫彗星试验(comet assay),是一种快速、敏感、简便、廉价的检测单个哺乳动物细胞DNA断裂的技术,目前已用于检测氧化、紫外线和电离辐射引起的损伤,以及三氯乙烷、丙烯酰胺等化学物及老化、吸烟所致损害的研究.文章介绍SCGE的发展、检测分析方法、原理及其在DNA损伤与修复、生物监测、遗传毒理研究、肿瘤治疗方案优化和疗效研究方面的应用前景. 相似文献
5.
Molecular mechanisms of DNA double-strand break repair 总被引:24,自引:0,他引:24
DNA double-strand breaks (DSBs) are major threats to the genomic integrity of cells. If not taken care of properly, they can cause chromosome fragmentation, loss and translocation, possibly resulting in carcinogenesis. Upon DSB formation, cell-cycle checkpoints are triggered and multiple DSB repair pathways can be activated. Recent research on the Nijmegen breakage syndrome, which predisposes patients to cancer, suggests a direct link between activation of cell-cycle checkpoints and DSB repair. Furthermore, the biochemical activities of proteins involved in the two major DSB repair pathways, homologous recombination and DNA end-joining, are now beginning to emerge. This review discusses these new findings and their implications for the mechanisms of DSB repair. 相似文献
6.
Use of a low-speed, iso-density percoll centrifugation method to increase the viability of isolated rat hepatocyte preparations 总被引:23,自引:0,他引:23
Bill L. Kreamer Jeffrey L. Staecker Norimasa Sawada Gerald L. Sattler M. T. Stephen Hsia Henry C. Pitot 《In Vitro Cellular & Developmental Biology - Plant》1986,22(4):201-211
Summary A simple yet effective method (iso-density percoll centrifugation) has been developed for consistently preparing isolated
rat liver parenchymal cells with over 98% initial viability. The method has been applied to cells isolated by a variety of
collagenase digestion techniques. This procedure involves the low-speed centrifugation (50 ×g) of the initial cell suspension through a percoll medium having a density of 1.06 g/ml and results in the separation of single
and viable parenchymal cells from cell aggregates, debris, and nonparenchymal cells. The enriched parenchymal cells have been
shown to be superior to untreated cells by a number of criteria including: preparation homogeneity, cell morphology, maintenance
of cytochrome P-450, hormonal responsiveness (measured by the induction of tyrosine aminotransferase after treatment with
glucagon or dexamethasone, or both), plasma membrane integrity (determined by both trypan blue exclusion and leakage of glutamic-oxaloacetic
transaminase), and the DNA repair capability after treatment with benzo[a]pyrene or 2-acetylaminofluorene.
This work was supported in part by the National Institutes of Health Biomedical Research Support Program, and National Institute
of Environmental Health Services grant (ES-01737) awarded to M.T.S.H., and by National Cancer Institute grants CA-017175,
CA-09135, CA-22484 awarded to H.C.P.N.S. was supported by a Cancer Research Campaign Grant (U. K.) through the International
Union Against Cancer. This work was presented in part at the 24th Annual Meeting of the Society of Toxicology, 18–22 March
1985, San Diego, CA. 相似文献
7.
UV-B damage and protection at the molecular level in plants 总被引:23,自引:0,他引:23
8.
Dose-dependence, sex- and tissue-specificity, and persistence of radiation-induced genomic DNA methylation changes 总被引:20,自引:0,他引:20
Pogribny I Raiche J Slovack M Kovalchuk O 《Biochemical and biophysical research communications》2004,320(4):1253-1261
Radiation is a well-known genotoxic agent and human carcinogen that gives rise to a variety of long-term effects. Its detrimental influence on cellular function is actively studied nowadays. One of the most analyzed, yet least understood long-term effects of ionizing radiation is transgenerational genomic instability. The inheritance of genomic instability suggests the possible involvement of epigenetic mechanisms, such as changes of the methylation of cytosine residues located within CpG dinucleotides. In the current study we evaluated the dose-dependence of the radiation-induced global genome DNA methylation changes. We also analyzed the effects of acute and chronic high dose (5Gy) exposure on DNA methylation in liver, spleen, and lung tissues of male and female mice and evaluated the possible persistence of the radiation-induced DNA methylation changes. Here we report that radiation-induced DNA methylation changes were sex- and tissue-specific, dose-dependent, and persistent. In parallel we have studied the levels of DNA damage in the exposed tissues. Based on the correlation between the levels of DNA methylation and DNA damage we propose that radiation-induced global genome DNA hypomethylation is DNA repair-related. 相似文献
9.
10.
Current aspects in metal genotoxicity 总被引:20,自引:0,他引:20
Andrea Hartwig 《Biometals》1995,8(1):3-11
While carcinogenic metal ions are mostly non-mutagenic in bacteria, different types of cellular damage have been observed in mammalian cells, which may account for their carcinogenic potential. Two modes of action seem to be predominant: the induction of oxidative DNA damage, best established for chromium compounds, and the interaction with DNA repair processes, leading to an enhancement of genotoxicity in combination with a variety of DNA damaging agents. In the case of Cd(II), Ni(II), Co(II), Pb(II) and As(III), DNA repair processes are disturbed at low, non-cytotoxic concentrations of the respective metal compounds. Even though different steps in DNA repair are affected by the diverse metals, one common mechanism might be the competition with essential metal ions. 相似文献