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Nat Commun. 2014 Sep 11;5:4760. doi: 10.1038/ncomms5760.

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

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Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle NE1 3BZ, UK.
School of Computing Science, Claremont Tower, Newcastle University, Newcastle upon Tyne NE1 7RU, UK.
Institute for Cellular Medicine, Newcastle University, Framlington Place, Newcastle NE2 4HH, UK.
Faculty of Computer and Information Science, University of Ljubljana, Trzaska cesta 25, SI-1000, Ljubljana, Slovenia.
1] Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle NE1 3BZ, UK [2] Institute of Cardiovascular Sciences, The University of Manchester, Manchester M13 9NT, UK.
Department of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, Canada J1E 4K8.
Institute for Cell and Molecular Biosciences, Newcastle University, Newcastle NE2 4HH, UK.


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 (Tra2α) and Tra2β 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 Tra2α and Tra2β induces substantial shifts in splicing of endogenous Tra2β target exons, and that both constitutive and alternative target exons are under dual Tra2α-Tra2β 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 γH2AX 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.

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