Review of arsenic toxicity, speciation and polyadenylation of canonical histones


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Abstract

Arsenic contamination impacts hundreds of millions of people in the world. Arsenic is a well-established human carcinogen and has been shown to cause skin, lung, bladder, liver, prostate and kidney cancers, in humans. Mechanisms that underlie arsenic-mediated carcinogenesis, including epigenetic alterations, remain largely unknown. Human exposure to Arsenic is reviewed, and the mechanisms of its acute and chronic toxicity and mechanisms of its carcinogenesis in humans are discussed. Arsenic is one of the few metals that is metabolized in vivo, and Arsenic methylation and how this results in a shorter half-life in vivo are discussed. A review of recent findings that Arsenic causes loss in the cellular levels of Stem Loop Binding Protein (SLBP) resulting in polyadenylation of canonical histones (H3.1) as a default, increasing levels of H3.1 protein outside of S-Phase. Malignant cell transformation is induced by knockdown of SLBP and by overexpression of polyadenylated H3.1. Arsenic induced polyadenylation of H3.1 causes enhanced levels of H3.1 protein displacing H3.3 protein from its cellular binding sites, since the two proteins differ by only 5 amino acids. Knockdown of H3.3 alone can induce carcinogenesis, and therefore displacement of functional H3.3 protein by increased H3.1 protein, is likely a mechanism of arsenic carcinogenesis.HighlightsArsenic induced human Cancers.Arsenic Toxicity.Mechanism of Arsenic Carcinogenesis.Arsenic interference with canonical histones synthesis.

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