Marco Bezzi1,2, Shun Xie Teo1, Julius Muller1, Wei Chuen Mok1, Sanjeeb Kumar Sahu1, Leah A. Vardy3,4, Zahid Q. Bonday5 and Ernesto Guccione1,2,6
1 - 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
2 - Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119074, Singapore
3 - Institute of Medical Biology (IMB), A*STAR, Singapore 138673, Singapore
4 - School of Biological Sciences, Nanyang
Technological University, Singapore 637551, Singapore;
5 - Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA
Published online in Genes and Development on 1 September 2013.
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 59 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.
Figure Legend: Mdm4 pre-mRNA senses defects in the spliceosomal machinery in cancer lines. Schematic model of the data presented in the study: Upon PRMT5 deletion (or reduction), we observed a loss of symmetric arginine dimethylation at key components of the splicing machinery (SmB/B9, SmD1, SmD3, and possibly others). This leads to aberrant snRNP maturation. The consequence is the activation of a sensing mechanism, which is linked to alternative splicing of key mRNAs (mainly RIs and SEs). As an example, we show Mdm4, which induces a potent p53 transcriptional activation. (Bottom) Other alternative splicing events might be equally important and will ultimately result in a p53-independent cell cycle arrest.
For more information on Ernesto GUCCIONE’s laboratory, please click here.