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

Andrew Best, Katherine James, Caroline Dalgliesh, Elaine Hong, Mahsa Kheirolahi-Kouhestani, Tomaz Curk, Yaobo Xu, Marina Danilenko, Rafiq Hussain, Bernard Keavney, Anil Wipat, Roscoe Klinck, Ian G. Cowell, Ka Cheong Lee, Caroline A. Austin, Julian P. Venables, Benoit Chabot, Mauro Santibanez Koref, Alison Tyson-Capper and David J. Elliott ()
Additional contact information
Andrew Best: Institute of Genetic Medicine, Newcastle University, Central Parkway
Katherine James: School of Computing Science, Claremont Tower, Newcastle University
Caroline Dalgliesh: Institute of Genetic Medicine, Newcastle University, Central Parkway
Elaine Hong: Institute for Cellular Medicine, Newcastle University
Mahsa Kheirolahi-Kouhestani: Institute of Genetic Medicine, Newcastle University, Central Parkway
Tomaz Curk: Faculty of Computer and Information Science, University of Ljubljana, Trzaska cesta 25, SI-1000
Yaobo Xu: Institute of Genetic Medicine, Newcastle University, Central Parkway
Marina Danilenko: Institute of Genetic Medicine, Newcastle University, Central Parkway
Rafiq Hussain: Institute of Genetic Medicine, Newcastle University, Central Parkway
Bernard Keavney: Institute of Genetic Medicine, Newcastle University, Central Parkway
Anil Wipat: School of Computing Science, Claremont Tower, Newcastle University
Roscoe Klinck: Faculty of Medicine and Health Sciences, Université de Sherbrooke
Ian G. Cowell: Institute for Cell and Molecular Biosciences, Newcastle University
Ka Cheong Lee: Institute for Cell and Molecular Biosciences, Newcastle University
Caroline A. Austin: Institute for Cell and Molecular Biosciences, Newcastle University
Julian P. Venables: Institute of Genetic Medicine, Newcastle University, Central Parkway
Benoit Chabot: Faculty of Medicine and Health Sciences, Université de Sherbrooke
Mauro Santibanez Koref: Institute of Genetic Medicine, Newcastle University, Central Parkway
Alison Tyson-Capper: Institute for Cellular Medicine, Newcastle University
David J. Elliott: Institute of Genetic Medicine, Newcastle University, Central Parkway

Nature Communications, 2014, vol. 5, issue 1, 1-15

Abstract: Abstract 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.

Date: 2014
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DOI: 10.1038/ncomms5760

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