Investigation of arsenic toxicity identified from the research of alternative splicing of arsenic (+3 oxidation state) methyltransferase

<p>Inorganic arsenic undergo methylation metabolism by arsenic (+3 oxidation state) methyltransferase (AS3MT). When proceeding with our research, we found that alternative splicing form of AS3MT mRNA. We also found a splicing variant by exposure to hydrogen peroxide. To investigate the mechanism, we focused a Serine/arginine-rich splicing factor (SRSF) 5 as a candidate factor involved in AS3MT splicing. Exposure to hydrogen peroxide reduced the protein levels of SRSF5. We considered that the increased sensitivity to arsenite (As(III)) in cells introduced SRSF5 siRNA. The increased sensitivity to As(III) was detected in SRSF5 siRNA-introduced cells although without detection of alternative splicing of AS3MT mRNA. To identify the genes involved in As(III) susceptibility, we compared the levels of mRNA extracted from control and SRSF5 siRNA-introduced cells by RNA-seq. We detected 155 genes whose mRNA content has been reduced by more than half due to SRSF5 siRNA. Among of 155 genes, we selected five genes as a candidate factor involved in As(III) sensitivity. The results showed that the sensitivity to As(III) was significantly increased by the introduction of Forkhead Box A1 siRNA. Taken together with our results, the SRSF5-FOXA1 pathway was found as a new factor involved in the toxicity of arsenite. In this symposium, we would like to introduce the research results from the discovery of splicing abnormalities to the identification of new mechanism of arsenic toxicity.</p>