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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >7SK snRNP/P-TEFb couples transcription elongation with alternative splicing and is essential for vertebrate development
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7SK snRNP/P-TEFb couples transcription elongation with alternative splicing and is essential for vertebrate development

机译：7SK snRNP / P-TEFb将转录延伸与选择性剪接结合在一起，对脊椎动物的发育至关重要

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摘要

Eukaryotic gene expression is commonly controlled at the level of RNA polymerase II (RNAPII) pausing subsequent to transcription initiation. Transcription elongation is stimulated by the positive transcription elongation factor b (P-TEFb) kinase, which is suppressed within the 7SK small nuclear ribonucleoprotein (7SK snRNP). However, the biogenesis and functional significance of 7SK snRNP remain poorly understood. Here, we report that LARP7, BCDIN3, and the noncoding 7SK small nuclear RNA (7SK) are vital for the formation and stability of a cell stress-resistant core 7SK snRNP. Our functional studies demonstrate that 7SK snRNP is not only critical for controlling transcription elongation, but also for regulating alternative splicing of pre-mRNAs. Using a transient expression splicing assay, we find that 7SK snRNP disintegration promotes inclusion of an alternative exon via the increased occupancy of P-TEFb, Ser2-phosphorylated (Ser2-P) RNAPII, and the splicing factor SF2/ASF at the minigene. Importantly, knockdown of Iarp7 or bcdin3 orthologues in zebrafish embryos destabilizes 7SK and causes severe developmental defects and aberrant splicing of analyzed transcripts. These findings reveal a key role for P-TEFb in coupling transcription elongation with alternative splicing, and suggest that maintaining core 7SK snRNP is essential for vertebrate development.
机译：真核基因表达通常控制在转录起始后暂停的RNA聚合酶II（RNAPII）的水平上。转录延伸受到正转录延伸因子b（P-TEFb）激酶的刺激，该激酶在7SK小核糖核糖核蛋白（7SK snRNP）中被抑制。然而，对7SK snRNP的生物发生和功能意义仍然知之甚少。在这里，我们报告LARP7，BCDIN3和非编码7SK小核RNA（7SK）对于细胞抗应激核心7SK snRNP的形成和稳定性至关重要。我们的功能研究表明，7SK snRNP不仅对于控制转录延伸至关重要，而且对于调控前mRNA的选择性剪接也至关重要。使用瞬时表达剪接测定法，我们发现7SK snRNP崩解通过增加P-TEFb，Ser2-磷酸化（Ser2-P）RNAPII和剪接因子SF2 / ASF在小基因上的占有率来促进其他外显子的包涵。重要的是，在斑马鱼胚胎中敲除Iarp7或bcdin3直向同源物会破坏7SK的稳定性，并导致严重的发育缺陷和分析的转录物异常剪接。这些发现揭示了P-TEFb在转录延伸与选择性剪接耦合中的关键作用，并表明维持核心7SK snRNP对脊椎动物的发育至关重要。

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    Matjaz Barboric; Tina Lenasi; Hui Chen; Eric B. Johansen; Su Guo; B. Matija Peterlin;

  • 作者单位

    Departments of Medicine, Microbiology, and Immunology, Rosalind Russell Medical Research Center, University of California, San Francisco, CA 94143-0703;

    Departments of Medicine, Microbiology, and Immunology, Rosalind Russell Medical Research Center, University of California, San Francisco, CA 94143-0703;

    Programs in Developmental Biology, Neuroscience, and Human Genetics, Department of Biopharmaceutical Sciences, University of California, San Francisco, CA 94143-2811;

    University of California at San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94143-0512 University of California at San Francisco Mass Spectrometry Core Facility, University of California, San Francisco, CA 94143-0512;

    Programs in Developmental Biology, Neuroscience, and Human Genetics, Department of Biopharmaceutical Sciences, University of California, San Francisco, CA 94143-2811;

    Departments of Medicine, Microbiology, and Immunology, Rosalind Russell Medical Research Center, University of California, San Francisco, CA 94143-0703;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    LARP7; BCDIN3; MePCE; HEXIM1; SF2/ASF;

    机译：赢贝斯迪娜;哭十六进制1拍手/对不起;

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