Arsenic, a ubiquitous environmental contaminant with widespread public health concern, is abundant naturally in minerals from the Earth’s crust and derived anthropogenically due to industrial applications, and it affects almost 150 million people in over 70 countries. Epidemiological studies have revealed that daily human exposure to arsenic in drinking water is associated with the prevalence of skin, lung and bladder cancers. Furthermore, aberrant histone modifications (e.g. acetylation) were found to be associated with arsenic exposure in previous studies, arsenic carcinogenesis is thought to stem partly from the perturbation of epigenetic pathways. Considering that zinc finger motif is present in and is indispensable for the enzymatic activities of crucial histone modifying enzymes especially the MYST family of histone acetyltransferases (e.g. TIP60), we reasoned that As3+ may target the zinc finger motif of these enzymes, thereby disturbing their enzymatic activities and altering histone acetylation. Herein, we found that As3+could bind directly to the zinc finger domain of TIP60 in vitro and in cells. In addition, exposure to As3+ could lead to a dose-dependent decrease in the protein level of TIP60 via the ubiquitin-proteasome pathway. Together, the results from the present study revealed, for the first time, that arsenite may alter epigenetic signaling by targeting cysteine residues in the zinc finger domains of TIP60 histone acetyltransferase, thereby altering H4K16Ac histone epigenetic mark. Thus, our results shed important light on the mechanisms underlying the arsenic-induced epigenotoxicity and carcinogenesis in humans.

Arsenite binds to the zinc finger domains of TIP60 histone acetyltransferase and induces its degradation via the 26S proteasome

254th National Meeting (2017)

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