Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery

  1. Ernesto Guccione1,2,6
  1. 1Division of Cancer Genetics and Therapeutics, Laboratory of Chromatin, Epigenetics, and Differentiation, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology, and Research), Singapore 138673, Singapore;
  2. 2Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore;
  3. 3Institute of Medical Biology (IMB), A*STAR, Singapore 138673, Singapore;
  4. 4School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore;
  5. 5Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA

    Abstract

    The tight control of gene expression at the level of both transcription and post-transcriptional RNA processing is essential for mammalian development. We here investigate the role of protein arginine methyltransferase 5 (PRMT5), a putative splicing regulator and transcriptional cofactor, in mammalian development. We demonstrate that selective deletion of PRMT5 in neural stem/progenitor cells (NPCs) leads to postnatal death in mice. At the molecular level, the absence of PRMT5 results in reduced methylation of Sm proteins, aberrant constitutive splicing, and the alternative splicing of specific mRNAs with weak 5′ donor sites. Intriguingly, the products of these mRNAs are, among others, several proteins regulating cell cycle progression. We identify Mdm4 as one of these key mRNAs that senses the defects in the spliceosomal machinery and transduces the signal to activate the p53 response, providing a mechanistic explanation of the phenotype observed in vivo. Our data demonstrate that PRMT5 is a master regulator of splicing in mammals and uncover a new role for the Mdm4 pre-mRNA, which could be exploited for anti-cancer therapy.

    Keywords

    Footnotes

    • Received May 8, 2013.
    • Accepted July 26, 2013.

    This article, published in Genes & Development, is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported), as described at http://creativecommons.org/licenses/by-nc/3.0/.

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