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, David J. Elliott

Research output: Contribution to journalArticlepeer-review

38 Citations (Scopus)
18 Downloads (Pure)

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.
Original languageEnglish
Article number4760
Number of pages15
JournalNature Communications
Volume5
Issue number1
Early online date11 Sept 2014
DOIs
Publication statusPublished - Dec 2014
Externally publishedYes

Keywords

  • Alternative Splicing
  • Cell Line
  • Tumor
  • Exons
  • Humans
  • MCF-7 Cells
  • Nerve Tissue Proteins
  • metabolism
  • Protein Kinases
  • genetics/metabolism
  • RNA
  • Messenger
  • RNA-Binding Proteins

Fingerprint

Dive into the research topics of 'Human Tra2 proteins jointly control a CHEK1 splicing switch among alternative and constitutive target exons'. Together they form a unique fingerprint.

Cite this