Replication-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 cells in 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.