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To counteract the adverse effects of various DNA lesions, cells have evolved an array of diverse repair pathways to restore DNA structure and to coordinate repair with cell cycle regulation. Chromatin changes are an integral part of the DNA damage response, particularly with regard to the types of repair that involve assembly of large multiprotein complexes such as those involved in double strand break (DSB) repair and nucleotide excision repair (NER). A number of phosphorylation, acetylation, methylation, ubiquitylation and chromatin remodeling events modulate chromatin structure at the lesion site. These changes demarcate chromatin neighboring the lesion, afford accessibility and binding surfaces to repair factors and provide on-the-spot means to coordinate repair and damage signaling. Thus, the hierarchical assembly of repair factors at a double strand break is mostly due to their regulated interactions with posttranslational modifications of histones. A large number of chromatin remodelers are required at different stages of DSB repair and NER. Remodelers physically interact with proteins involved in repair processes, suggesting that chromatin remodeling is a requisite for repair factors to access the damaged site. Together, recent findings define the roles of histone post-translational modifications and chromatin remodeling in the DNA damage response and underscore possible differences in the requirements for these events in relation to the chromatin context., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Epigenetic mechanisms maintain heritable changes in gene expression and chromatin organization over many cell generations. Importantly, deregulated epigenetic mechanisms play a key role in a wide range of human malignancies, including liver cancer. Hepatocellular carcinoma (HCC), which originates from the hepatocytes, is by far the most common liver cancer, with rates and aetiology that show considerable geographic variation. Various environmental agents and lifestyles known to be risk factors for HCC (such as infection by hepatitis B virus (HBV) and hepatitis C virus (HCV), chronic alcohol intake, and aflatoxins) are suspected to promote its development by eliciting epigenetic changes, however the precise gene targets and underlying mechanisms have not been elucidated. Many recent studies have exploited conceptual and technological advances in epigenetics and epigenomics to investigate the role of epigenetic events induced by environmental factors in HCC tumors and non-tumor precancerous (cirrhotic) lesions. These studies have identified a large number of genes and pathways that are targeted by epigenetic deregulation (changes in DNA methylation, histone modifications and RNA-mediated gene silencing) during the development and progression of HCC. Frequent identification of aberrant epigenetic changes in specific genes in cirrhotic tissue is consistent with the notion that epigenetic deregulation of selected genes in pre-malignant lesions precedes and promotes the development of HCC. In addition, several lines of evidence argue that some environmental factors (such as HBV virus) may abrogate cellular defense systems, induce silencing of host genes and promote HCC development via an "epigenetic strategy". Finally, profiling studies reveal that HCC tumors and pre-cancerous lesions may exhibit epigenetic signatures associated with specific risk factors and tumor progression stage. Together, recent evidence underscores the importance of aberrant epigenetic events induced by environmental factors in liver cancer and highlights potential targets for biomarker discovery and future preventive and therapeutic strategies., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Over the last 40 years mankind has been facing new types of radiochemical environmental settings with every decade. During the last decade, biomonitoring was additionally focused on assessing associations between environmental exposure(s) and both early and late biological effects in children. Despite efforts to control and avoid child exposure to genotoxic agents the incidence of childhood cancers is increasing. Some cancers in adulthood may be the consequence of a multi-step process which starts with intrauterine and childhood exposure. This highlights the importance of a comprehensive interpretation of multiple health effects, especially considering recent studies suggesting that most health disorders are related to DNA changes. When exposed to genotoxic agents, a developing organism (fetus or child) is constantly being forced to reorganize into new equilibriums in order to adjust to a xenobiotic environment. In addition, the influence of sex hormones on radiochemical sensitivity is still unknown. For this reason special attention should be paid to puberty. The results of recent studies on animal models and follow up studies on children after nuclear accidents show long-lasting cytogenetic damage even after low dose exposures and their transgenerational persistance. To evaluate age-related difference and transplacental genotoxic potency fluconazole (FC) was investigated by in vivo micronucleus (MN) assay in adult mice, young mice and in transplacentally exposed newborn pups. Compared to the baseline values, FC caused no detectable genome damage in adult animals, but there was a significant increase in MN frequency in young animals and in newborn pups. Our study thus exemplifies an age-related chemosensitivity, and argues that cancer-promoting disturbances of complex prenatal developmental mechanisms and maturation during childhood require a new approach using systems biology.

Cancer is traditionally viewed as a primarily genetic disorder, however it is now becoming accepted that cancer is also a consequence of abnormal epigenetic events. Genetic changes and aneuploidy are associated with alterations in DNA sequence, and they are a hallmark of the malignant process. Epigenetic alterations are universally present in human cancer and result in heritable changes in gene expression and chromatin structure over many cell generations without changes in DNA sequence, leading to functional consequences equivalent to those induced by genetic alterations. Importantly, intriguing evidence emerged suggesting that epigenetic changes may precede and provoke genetic changes. In this scenario, epigenetic events are primary events while genetic changes (such as mutations) may simply be a consequence of disrupted epigenetic states. This fact may explain why many genetic screens proved to be limited with regard to cancer causality and pathogenesis. Aberrant epigenetic events affect multiple genes and cellular pathways in a non-random fashion and this can predispose to induction and accumulation of genetic changes in the course of tumour initiation and progression. These considerations are critical for a better understanding of tumourigenesis and molecular events underlying the acquisition of drug resistance, as well as development of novel strategies for cancer therapy and prevention.

Knowledge on heritable changes in gene expression that result from epigenetic events is of increasing relevance in the development of strategies for prevention, early diagnosis and treatment of cancer. Histone acetylation and DNA methylation are epigenetic modifications whose patterns can be regarded as heritable marks that ensure accurate transmission of the chromatin states and gene expression profiles over many cell generations. Importantly, patterns and levels of DNA methylation and histone acetylation are profoundly altered in human cancers. Accumulating evidence suggests that an epigenetic cross-talk, i.e. interplay between DNA methylation and histone acetylation, may be involved in the process of gene transcription and aberrant gene silencing in tumours. Although the molecular mechanism of gene activation is relatively well understood, the hierarchical order of events and dependencies leading to gene silencing in the course of cancer development remain largely unknown. While some studies suggest that DNA methylation patterns guide histone modifications (including histone acetylation and methylation) during gene silencing, other studies argue that DNA methylation takes its cues primarily from histone modification states. In this review, we summarize current knowledge on the interplay between DNA methylation and histone modifications during gene silencing and its importance in the integration of environmental and intrinsic stimuli in the control of gene expression. We also discuss the importance of an epigenetic cross-talk in the protection against genetic changes in response to environmental genotoxins as well as the implication for cancer therapy and prevention.

Cancers are traditionally viewed as a primarily genetic disorder, however this view has recently been modified by compelling evidence arguing that epigenetic events play important roles in most human cancers. Deregulation of epigenetic information (encoded in DNA methylation and histone modification patterns) in cells with pluripotent potential may alter defining properties of stem cells, self-renewal and differentiation potential, leading to cancer initiation and progression. The level of compaction of chromatin dictates accessibility to genomic DNA and therefore has a key role in establishing and maintaining distinct gene expression patterns and consequently pluripotent state and differentiation fates of stem cells. Unique properties of stem cells defined as "stemness" may be determined by acetylation and methylation of histones near gene promoters that regulate gene transcription, however these histone modifications elsewhere in the genome may also be important. In this review, we discuss new insights into possible mechanisms by which histone acetyltransferases (HATs) and histone acetylation in concert with other chromatin modifications may regulate pluripotency, and speculate how deregulation of histone marking may lead to tumourigenesis.

Poly(ADP-ribose) polymerase (PARP) is responsible for post-translational modification of proteins in the response to numerous endogenous and environmental genotoxic agents. PARP and poly(ADP-ribosyl)ation are proposed to be important for the regulation of many cellular processes such as DNA repair, cell death, chromatin functions and genomic stability. Activation of PARP is one of the early DNA damage responses, among other DNA sensing molecules, such as DNA-PK, ATM and p53. The generation and characterization of PARP deficient mouse models have been instrumental in defining the biological role of the molecule and its involvement in the pathogenesis of various diseases including diabetes, stroke, Parkinson disease, general inflammation as well as tumorigenesis, and have, therefore, provided information for the development of pharmaceutical strategies for the treatment of diseases.

A non-tumorigenic human thyroid epithelial cell line (HTori-3) has been transformed into tumorigenic cells by exposure in vitro to alpha particles or gamma-radiation. These transformants were tumorigenic in athymic nude mice and tumors were transplantable into other nude mice. To further characterize processes involved in neoplastic progression, the tumor cell lines derived from these radiation-induced primary tumors were screened for mutations in the p53 tumor suppressor gene. p53 mutation was detected by single-strand conformation polymorphism (SSCP) analysis of exons 5 to 8 inclusive. Mutations detected by SSCP analysis were confirmed by sequencing. Mutations were detected in all four exons analysed, although there was no correlation between dose, LET or mutation position or frequency. Mutations in p53 exons 6 and 7 have been reported in the childhood papillary thyroid carcinomas in Belarus presumably as a result of radioiodine fall-out. Similarly here, p53 mutations are induced experimentally during the development of human thyroid tumors generated by irradiation of a human thyroid epithelial cell line in vitro., (Copyright 1999 Elsevier Science B.V.)