The Cellular Response to the Genotoxic Insult PDF

The Cellular Response to the Genotoxic Insult PDF



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Preface

So far there is general consensus that no threshold can be identified for genotoxic carcinogens. However, there is experimental evidence of no-observedeffect- levels (NOELs) for carcinogenic and mutagenic effects in repeated dose studies in animals and there are examples indicating that the shape of the dose–responses of DNA adducts and mutations differ. It is also evident that the dose–response for mutations will reach the background mutation frequency. This implies that, at very low doses, the mutation rate induced by a genotoxic carcinogen becomes indistinguishable from the background mutation frequency. Moreover, the array of cellular defence mechanisms to a genotoxic insult makes it unlikely that a single event overcomes these barriers to cancer. Consequently, the notion that even low exposures to genotoxic agents present a cancer risk is to be questioned.
Besides metabolic inactivation there are two major cellular defence mechanisms: DNA repair and apoptosis—both of which are triggered by tumour suppressor genes. The mechanism by which the tumour suppressor gene p53 affects cell cycling and stimulates the DNA repair machinery after activation by DNA damage had already been described by 1994. The expressed protein p53 triggers the expression of two proteins p21 and Gadd45; p21 inhibits cyclin-dependent kinase activity, thus slowing down cell cycling and DNA replication, while Gadd45 increases DNA repair. In addition p53 binds to ERCC3, one of several excision repair molecules that together identify and remove damaged segments from DNA.
Another function under the control of p53 is apoptosis. Apoptosis (programmed cell death) seems to represent the primary mechanism by which mutant cells are continually removed from tissues. Intracellular sensors detect DNA damage and signal imbalance by overexpressed oncogenes, survival factor imbalance, or hypoxia. They activate death receptors or induce cytochrome c release, which activate caspases that trigger selective destruction of cellular structures. Up-regulation is controlled by tumour suppressor genes (e.g. p53). DNA damage activates p53, which up-regulates expression of CDK-inhibitor p21 and pro-apoptotic proteins (NOXA, PUMA). In normal cells Rb is activated and blocks deamidation of Bcl-xL, inhibiting the NOXA and PUMA capabilities of Bax-activation, cytochrome c release and caspase activation. In tumour cells without Rb-activation, DNA damage activates Bcl deamidation and releases Bax block, leading to apoptosis. Cytochrome c release induces assembly of Apaf monomers to the apoptosome, which activates caspases. The inhibitor of apoptosis (IAP) family of proteins inhibit caspases. Smac co-released with cytochrome c releases this inhibition.
The increasing understanding of epigenetic regulation of gene expression by methylation of histones, which allow chromosomal regions to switch between on and off status, indicate further mechanisms by which cells can react to a genotoxic insult. Among others the methylation process itself is controlled by Argonaute proteins, which segregate into two clades, the Ago cade and the Piwi clade. Of these, Ago clade proteins complex with microRNAs and small interfering RNAs, which derive from double-strand RNA precursors. The microRNA–Ago complexes reduce the translation and stability of protein coding mRNAs, which results in a regulatory network that impacts about 30% of all genes.
Although cellular defence mechanisms are increasingly understood, the critical and rate limiting parameters and their dose–response to the insulting agent need to be evaluated. This book describes the different cellular defence mechanisms and their regulation. We have prepared a summarizing chapter (Chapter 1), which evaluates the plausibility of a dose-dependent threshold mechanism of genotoxic carcinogens and their rate-limiting parameters to allow determination of the onset of such counterbalancing reactions. Finally possible data gaps for further research are described.
Besides its scientific value, a better understanding of cellular defence is of regulatory importance since a scientifically defendable threshold concept for genotoxic carcinogens will allow the NOEL to be identified and from that the proposal of health-based exposure limits for genotoxic carcinogens.


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