A recently evolved class of alternative 3′-terminal exons involved in cell cycle regulation by topoisomerase inhibitors

Alternative 3′-terminal exons, which use intronic polyadenylation sites, are generally less conserved and expressed at lower levels than the last exon of genes. Here we discover a class of human genes, in which the last exon appeared recently during evolution, and the major gene product uses an alternative 3′-terminal exon corresponding to the ancestral last exon of the gene. This novel class of alternative 3′-terminal exons are downregulated on a large scale by doxorubicin, a cytostatic drug targeting topoisomerase II, and play a role in cell cycle regulation, including centromere–kinetochore assembly. The RNA-binding protein HuR/ELAVL1 is a major regulator of this specific set of alternative 3′-terminal exons. HuR binding to the alternative 3′-terminal exon in the pre-messenger RNA promotes its splicing, and is reduced by topoisomerase inhibitors. These findings provide new insights into the evolution, function and molecular regulation of alternative 3′-terminal exons.