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The splicing activator DAZAP1 integrates splicing control into MEK/Erk-regulated cell proliferation and migration

Author

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  • Rajarshi Choudhury

    (University of North Carolina)

  • Sreerupa Ghose Roy

    (University of North Carolina)

  • Yihsuan S. Tsai

    (University of North Carolina
    Curriculum in Bioinformatics and Computational Biology, University of North Carolina)

  • Ashutosh Tripathy

    (University of North Carolina)

  • Lee M. Graves

    (University of North Carolina
    Lineberger Comprehensive Cancer Center, University of North Carolina)

  • Zefeng Wang

    (University of North Carolina
    Lineberger Comprehensive Cancer Center, University of North Carolina)

Abstract

Alternative splicing of pre-messenger RNA (mRNA) is a critical stage of gene regulation in response to environmental stimuli. Here we show that DAZAP1, an RNA-binding protein involved in mammalian development and spermatogenesis, promotes inclusion of weak exons through specific recognition of diverse cis-elements. The carboxy-terminal proline-rich domain of DAZAP1 interacts with and neutralizes general splicing inhibitors, and is sufficient to activate splicing when recruited to pre-mRNA. This domain is phosphorylated by the MEK/Erk (extracellular signal-regulated protein kinase) pathway and this modification is essential for the splicing regulatory activity and the nuclear/cytoplasmic translocation of DAZAP1. Using mRNA-seq, we identify endogenous splicing events regulated by DAZAP1, many of which are involved in maintaining cell growth. Knockdown or over-expression of DAZAP1 causes a cell proliferation defect. Taken together, these studies reveal a molecular mechanism that integrates splicing control into MEK/Erk-regulated cell proliferation.

Suggested Citation

  • Rajarshi Choudhury & Sreerupa Ghose Roy & Yihsuan S. Tsai & Ashutosh Tripathy & Lee M. Graves & Zefeng Wang, 2014. "The splicing activator DAZAP1 integrates splicing control into MEK/Erk-regulated cell proliferation and migration," Nature Communications, Nature, vol. 5(1), pages 1-16, May.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4078
    DOI: 10.1038/ncomms4078
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