Cheryl M Koh1*, Marco Bezzi1,2*, Diana HP Low1, Wei Xia Ang1, Shun Xie Teo1, Florence PH Gay1, Muthafar Al-Haddawi1, Soo Yong Tan1, Motomi Osato3, Arianna Sabò4, Bruno Amati4,5, Keng Boon Wee6 and Ernesto Guccione 1,2,3#.
1 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, 8 Medical Drive, Singapore 117597, Singapore;
3 Cancer Science Institute of Singapore (CSI), National University of Singapore, 14 Medical Drive, Singapore, 117599, Singapore;
4 Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Via Adamello 16, 20139 Milan, Italy;
5 Department of Experimental Oncology, European Institute of Oncology (IEO), Via Adamello 16, 20139 Milan, Italy;
6 Institute of High Performance Computing (IHPC), A*STAR (Agency for Science, Technology and Research), Connexis, Singapore 138632;
7 Bioinformatics Institute (BII), A*STAR (Agency for Science, Technology and Research), Singapore 138671.
* Contributed equally to this work.
# Correspondence should be addressed to Ernesto Guccione (firstname.lastname@example.org)
Published online ahead of print in Nature on 11 May 2015.
Deregulated expression of the MYC transcription factor occurs in a majority of human cancers and correlates with high proliferation, reprogrammed cellular metabolism and poor prognosis1. Over-expressed MYC binds to virtually all active promoters within a cell, although with different binding affinities, and modulates the expression of distinct subsets of genes. However, the critical effectors of MYC in tumourigenesis remain largely unknown. Here, we show that during lymphomagenesis in Eµ-myc transgenic mice, MYC directly up-regulates the transcription of the core snRNP assembly genes, including Prmt5, an arginine methyltransferase that methylates Sm proteins. This coordinated regulatory effect is critical for core snRNP biogenesis, effective pre-mRNA splicing, cell survival and proliferation. Our results demonstrate for the first time that MYC maintains the splicing fidelity of exons with a weak 5'-donor site. Additionally, we identify pre-mRNAs that are particularly sensitive to the perturbation of the MYC-PRMT5 axis, resulting in either intron retention (RI; e.g. Dvl1) or exon skipping (SE; e.g. Atr, Ep400). Using antisense oligonucleotides (ASOs), we demonstrate the contribution of these splicing defects to the anti-proliferative/apoptotic phenotype observed in PRMT5-depleted Eµ-myc B-cells. We conclude that, in addition to its well-documented oncogenic functions in transcription and translation, MYC also safeguards proper pre-mRNA splicing as an essential step in lymphomagenesis.
Click on image to view larger version
Figure Legend: Top panel: black lines
indicate MYC direct transcriptional upregulation of PRMT5 and other components of the core snRNP assembly machinery, which ensures splicing fidelity. Bottom panel: red arrows indicate the perturbation of the MYC–PRMT5 axis, which leads to a reduction in splicing fidelity within the cell, skipped exons and retained introns of genes, such as Ep400, Dvl1 and Atr (which harbour exons with weak 5'-donor sites), downregulation of their protein levels and, consequently, cell-cycle arrest and apoptosis.
For more information on Ernesto GUCCIONE's laboratory, please click here.