Summary
Replication-dependent canonical histone messenger RNAs (mRNAs) do not terminate with a poly(A) tail at the 3’ end. We previously demonstrated that arsenic exposure induces polyadenylation of canonical histone H3.1 mRNA in vitro. Here we report that ectopic expression of polyadenylated H3.1 mRNA enhances anchorage-independent cell growth and tumor formation in nude mice. Notably, polyadenylated H3.1 mRNA increases H3.1 protein level, resulting in depletion of histone variant H3.3 at active promoters, enhancers, and insulator regions. Moreover, polyadenylation of H3.1 mRNA causes transcriptional deregulation, G2/M cell cycle arrest, chromosome aneuploidy and aberrations. Importantly, arsenic is capable of inducing high levels of H3.1 mRNA polyadenylation in vivo. We propose polyadenylation of H3.1 mRNA and resulting displacement of H3.3 as a potential mechanism for arsenic-induced carcinogenesis. Our study adds new insight into the importance of proper histone stoichiometry in maintaining genome integrity.
Highlights
Polyadenylation of canonical histone H3.1 mRNA promotes anchorage-independent cell growth and tumor formation in nude mice
Histone variant H3.3 is displaced from critical gene regulatory elements by overexpression of polyadenylated H3.1 mRNA
Increased polyadenylated H3.1 mRNA causes abnormal transcription, cell cycle arrest, and chromosomal instability
Arsenic induces polyadenylation of H3.1 mRNA in vivo