Human Tra2 proteins jointly control a CHEK1 splicing switch among alternative and constitutive target exons

Alternative splicing-the production of multiple messenger RNA isoforms from a single gene-is regulated in part by RNA binding proteins. While the RBPs transformer2 alpha (Tra2 alpha) and Tra2 beta have both been implicated in the regulation of alternative splicing, their relative contributions to this process are not well understood. Here we find simultaneous-but not individual-depletion of Tra2 alpha and Tra2 beta induces substantial shifts in splicing of endogenous Tra2 beta target exons, and that both constitutive and alternative target exons are under dual Tra2 alpha-Tra2 beta control. Target exons are enriched in genes associated with chromosome biology including CHEK1, which encodes a key DNA damage response protein. Dual Tra2 protein depletion reduces expression of full-length CHK1 protein, results in the accumulation of the DNA damage marker gamma H2AX and decreased cell viability. We conclude Tra2 proteins jointly control constitutive and alternative splicing patterns via paralog compensation to control pathways essential to the maintenance of cell viability.