title: Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery.
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.
authors.affiliation: Division 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;
authors.forename: Marco
authors.initials: M
authors.lastname: Bezzi
authors.forename: Shun Xie
authors.initials: SX
authors.lastname: Teo
authors.forename: Julius
authors.initials: J
authors.lastname: Muller
authors.forename: Wei Chuen
authors.initials: WC
authors.lastname: Mok
authors.forename: Sanjeeb Kumar
authors.initials: SK
authors.lastname: Sahu
authors.forename: Leah A
authors.initials: LA
authors.lastname: Vardy
authors.forename: Zahid Q
authors.initials: ZQ
authors.lastname: Bonday
authors.forename: Ernesto
authors.initials: E
authors.lastname: Guccione
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D002490:Central Nervous System / Q000473:pathology; D016158:Genes, p53 / Q000235:genetics; D045325:HCT116 Cells; D057809:HEK293 Cells; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064231:Nestin; D011485:Protein Binding; D011496:Protein Methyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011484:Protein-Arginine N-Methyltransferases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism*; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics*; D015398:Signal Transduction; D017381:Spliceosomes / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D007381:Intermediate Filament Proteins; C461497:Mdm4 protein, mouse; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D011518:Proto-Oncogene Proteins; D012322:RNA Precursors; D011496:Protein Methyltransferases; C498518:Prmt5 protein, mouse; D011484:Protein-Arginine N-Methyltransferases; D044767:Ubiquitin-Protein Ligases
keywords: MDM4; PRMT5; arginine methylation; development; p53; splicing