Epigenetic Regulation by Poly(ADP-ribose) in Response to Arsenite

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DESCRIPTION (provided by applicant): Chronic arsenic exposure endangers millions of people with skin alterations, peripheral vascular disease, and cancer, including skin, lung, and bladder cancer by, in part, altering gene expression. Increasing evidence demonstrates that epigenetic mechanisms could regulate gene activation or silencing. Therefore, epigenetic regulation could be a part of the mechanisms for arsenic-induced toxicity. Poly(ADP-ribose) polymerase-1 (PARP-1) covalently modifies histones with poly(ADP-ribose), a negatively charged polymer. Poly(ADP-ribosyl)ation of nucleosomal histones alters chromatin structure and is thus thought to regulate chromatin template-dependent processes including gene transcription. Recently, PARP-1 has been shown to regulate stress-induced gene transcription. The overall hypothesis is that chromatin-associated PARP-1 covalently modifies nucleosomal histones with poly(ADP-ribose), and poly(ADP-ribosyl)ated histone(s) epigenetically regulates gene transcription in response to arsenite. The specific aims are to (1) determine the level and patterns of poly(ADP-ribosyl)ated histones in response to arsenite exposure, (2) elucidate the cellular mechanism that can alter the level of pADPr-histones in response to arsenite, (3) determine poly(ADP-ribosyl)ated histone(s) at the chromatin promoters of arsenite-induced target genes, and (4) determine the impact of a PARP enzymatic inhibitor on other arsenite-induced epigenetic markings. The significance of the proposed studies is to offer new insights into the epigenetic mechanism(s) by which poly(ADP-ribosyl)ation of histone(s) may regulate and be regulated to achieve stress response gene transcription in response to arsenite exposure. This mechanism of poly(ADP-ribosyl)ation may be especially adapted to facilitate sudden bursts of efficient transcription activity and therefore is critical for the outcome of environmental exposure.