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.
Bibliographical noteFunding Information:
We thank the NYULMC Genome Technology Center, partially supported by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center. The authors thank Drs. Sitharam Ramaswami, Thomas Des Marais and Gabriele Grunig for technical assistance and Suresh Cuddapah for helpful comments. The graphic abstract was created with BioRender.com. This work was supported by grants from the US National Institutes of Health : R01ES026138 (M.C. and C.J.), P30ES000260 (M.C. and Pilot Project Program to C.J.), R01ES029359 (M.C. and C.J.), R01ES030583 (C.J. and M.C.), R01ES022935 (M.C.), R35GM133712 (C.Z.), and K22CA204439 (C.Z.).
- Cell Biology