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Nat Commun. 2014;5:3078. doi: 10.1038/ncomms4078.

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

Author information

1
Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
2
1] Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, USA [2] Curriculum in Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
3
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
4
1] Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, USA [2] Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

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.

PMID:
24452013
PMCID:
PMC4146490
DOI:
10.1038/ncomms4078
[Indexed for MEDLINE]
Free PMC Article

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