title: Hydrogen peroxide triggers a novel alternative splicing of arsenic (+3 oxidation state) methyltransferase gene.
abstract: We previously reported that two splicing variants of human AS3MT mRNA, exon-3 skipping form (Δ3) and exons-4 and -5 skipping form (Δ4,5), were detected in HepG2 cells and that both variants lacked arsenic methylation activity (Sumi et al., 2011). Here we studied whether hydrogen peroxide (H2O2) triggers alternative splicing of AS3MT mRNA. The results showed that exposure of HepG2 cells to H2O2resulted in increased levels of a novel spliced form skipping exon-3 to exon-10 (Δ3-10) in an H2O2-concentration-dependent manner, although no change was detected in the mRNA levels of Δ3 AS3MT. We found decreased protein levels of serine/arginine-rich 40 (SRp40), which we determined to be a candidate splice factor for controlling the splicing of AS3MT mRNA. We next compared the amounts of methylated arsenic metabolites between control and H2O2-exposed HepG2 cells after the addition of arsenite as a substance. The results showed lower levels of methylated arsenic metabolites in HepG2 cells exposed to H2O2. These data suggest that the splicing of AS3MT pre-mRNA was disconcerted by oxidative stress and that abnormal alternative splicing of AS3MT mRNA may affect arsenic methylation ability.
authors.affiliation: Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan.
authors.forename: Daigo
authors.initials: D
authors.lastname: Sumi
authors.affiliation: Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan.
authors.forename: Chieri
authors.initials: C
authors.lastname: Takeda
authors.affiliation: Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan.
authors.forename: Daiki
authors.initials: D
authors.lastname: Yasuoka
authors.affiliation: Laboratory of Molecular Nutrition and Toxicology, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan. Electronic address: himenos@ph.bunri-u.ac.jp.
authors.forename: Seiichiro
authors.initials: S
authors.lastname: Himeno
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects* / Q000235:genetics; D001151:Arsenic / Q000378:metabolism / Q000493:pharmacokinetics; D056945:Hep G2 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism
chemical_list: D006861:Hydrogen Peroxide; D008780:Methyltransferases; C505756:AS3MT protein, human; D046988:Proteasome Endopeptidase Complex; D001151:Arsenic
keywords: Alternative splicing; Arsenic (+3 oxidation state) methyltransferase; Methyltransferase activity