摘要：SummaryReplication-dependent canonical histone messenger RNAs (mRNAs) do not terminate with a poly(A) tail at the 3′ end. We previously demonstrated that exposure to arsenic, an environmental carcinogen, induces polyadenylation of canonical histone H3.1 mRNA, causing transformation of human cellsin vitro. Here we report that polyadenylation of H3.1 mRNA increases H3.1 protein, resulting in displacement of histone variant H3.3 at active promoters, enhancers, and insulator regions, leading to transcriptional deregulation, G2/M cell-cycle arrest, chromosome aneuploidy, and aberrations. In support of these observations, knocking down the expression of H3.3 induced cell transformation, whereas ectopic expression of H3.3 attenuated arsenic-induced cell transformation. Notably, arsenic exposure also resulted in displacement of H3.3 from active promoters, enhancers, and insulator regions. These data suggest that H3.3 displacement might be central to carcinogenesis caused by polyadenylation of H3.1 mRNA upon arsenic exposure. Our findings illustrate the importance of proper histone stoichiometry in maintaining genome integrity.Graphical AbstractDisplay OmittedHighlights•Arsenic induces polyadenylation of canonical histone H3.1 mRNAin vivo•Polyadenylation of H3.1 mRNA promotes tumor formation in nude mice•The variant H3.3 is displaced from regulatory elements by polyadenylated H3.1 mRNA•Polyadenylated H3.1 mRNA causes abnormal transcription and chromosomal instabilityToxicology; Cell Biology; Omics
