Choudhury Rajarshi, Roy Sreerupa Ghose, Tsai Yihsuan S, Tripathy Ashutosh, Graves Lee M, Wang Zefeng
Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
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.
Nat Commun. 2014;5:3078. doi: 10.1038/ncomms4078.
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.
信使前体RNA（mRNA）的可变剪接是基因在响应环境刺激时进行调控的关键阶段。在此我们表明，DAZAP1是一种参与哺乳动物发育和精子发生的RNA结合蛋白，它通过特异性识别多种顺式元件来促进弱外显子的包含。DAZAP1富含脯氨酸的羧基末端结构域与一般剪接抑制剂相互作用并使其失活，当被招募到前体mRNA上时，该结构域足以激活剪接。该结构域被MEK/Erk（细胞外信号调节蛋白激酶）途径磷酸化，这种修饰对于DAZAP1的剪接调节活性以及核/质转运至关重要。利用mRNA测序，我们鉴定出受DAZAP1调控的内源性剪接事件，其中许多事件参与维持细胞生长。敲低或过表达DAZAP1会导致细胞增殖缺陷。综上所述，这些研究揭示了一种将剪接控制整合到MEK/Erk调控的细胞增殖中的分子机制。
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