Arsenic is a widespread environmental contaminant and humans are exposed to arsenicals through skin contact, inhalation and ingestion, which can cause skin, liver, and bladder tumors as well as cardiovascular and neurological diseases. Although trivalent arsenic is known to result in cytotoxicity by inducing oxidative damage, the mechanism underlying the carcinogenic effect of inorganic arsenite remains obscure. Core histones can be ubiquitinated by RING finger E3 ubiquitin ligases, where RNF20/RNF40 heterodimer catalyzes the ubiquitination of histone H2B at K120 and RNF8 induces ubiquitination of histone H2A at K119. Both ubiquitination events are important in the recruitment of DNA repair proteins to DNA double strand break (DSB) sites. Here we found that arsenite can directly bind to the RING finger domain of RNF20/RNF40 and RNF8 in vitro and in cells. We also observed that, upon treatment with NaAsO2, multiple cell lines displayed significantly diminished ubiquitination of H2A K119 and H2B K120. We also observed that arsenite treatment abolished the recruitment of ubiquitinated H2A to DSB sites following ionizing radiation exposure and reduced the rate of DNA DSB repair in human cells through the homologous recombination pathway. Together, the results from the present study revealed that arsenite may exert its carcinogenic effect by directly binding to the RING finger domain of histone E3 ubiquitin ligases, thereby altering histone epigenetic marks and compromising DNA DSB repair.

Arsenite induces compromised DNA double-strand break repair through direct binding to histone E3 ubiquitin ligases

246th National Meeting (2013)

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