title: MYC regulates the core pre-mRNA splicing machinery as an essential step in lymphomagenesis.
abstract: Deregulated expression of the MYC transcription factor occurs in most human cancers and correlates with high proliferation, reprogrammed cellular metabolism and poor prognosis. Overexpressed 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 tumorigenesis remain largely unknown. Here we show that during lymphomagenesis in Eµ-myc transgenic mice, MYC directly upregulates the transcription of the core small nuclear ribonucleoprotein particle assembly genes, including Prmt5, an arginine methyltransferase that methylates Sm proteins. This coordinated regulatory effect is critical for the core biogenesis of small nuclear ribonucleoprotein particles, effective pre-messenger-RNA splicing, cell survival and proliferation. Our results demonstrate that MYC maintains the splicing fidelity of exons with a weak 5' donor site. Additionally, we identify pre-messenger-RNAs that are particularly sensitive to the perturbation of the MYC-PRMT5 axis, resulting in either intron retention (for example, Dvl1) or exon skipping (for example, Atr, Ep400). Using antisense oligonucleotides, 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-messenger-RNA splicing as an essential step in lymphomagenesis.
authors.affiliation: Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore 138673, Singapore.
authors.forename: Cheryl M
authors.initials: CM
authors.lastname: Koh
authors.affiliation: 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.
authors.forename: Marco
authors.initials: M
authors.lastname: Bezzi
authors.affiliation: Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore 138673, Singapore.
authors.forename: Diana H P
authors.initials: DH
authors.lastname: Low
authors.affiliation: Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore 138673, Singapore.
authors.forename: Wei Xia
authors.initials: WX
authors.lastname: Ang
authors.affiliation: Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore 138673, Singapore.
authors.forename: Shun Xie
authors.initials: SX
authors.lastname: Teo
authors.affiliation: Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore 138673, Singapore.
authors.forename: Florence P H
authors.initials: FP
authors.lastname: Gay
authors.affiliation: Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore 138673, Singapore.
authors.forename: Muthafar
authors.initials: M
authors.lastname: Al-Haddawi
authors.affiliation: Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore 138673, Singapore.
authors.forename: Soo Yong
authors.initials: SY
authors.lastname: Tan
authors.affiliation: Cancer Science Institute of Singapore (CSI), National University of Singapore, 14 Medical Drive, Singapore 117599, Singapore.
authors.forename: Motomi
authors.initials: M
authors.lastname: Osato
authors.affiliation: Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Via Adamello 16, 20139 Milan, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Sabò
authors.affiliation: 1] Center for Genomic Science of IIT@SEMM, Fondazione Istituto Italiano di Tecnologia (IIT), Via Adamello 16, 20139 Milan, Italy [2] Department of Experimental Oncology, European Institute of Oncology (IEO), Via Adamello 16, 20139 Milan, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Amati
authors.affiliation: 1] Institute of High Performance Computing (IHPC), A*STAR (Agency for Science, Technology and Research), Connexis, Singapore 138632, Singapore [2] Bioinformatics Institute (BII), A*STAR (Agency for Science, Technology and Research), Singapore 138671, Singapore.
authors.forename: Keng Boon
authors.initials: KB
authors.lastname: Wee
authors.affiliation: 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.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Guccione
mesh_terms: D000818:Animals; D005091:Exons / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D007438:Introns / Q000235:genetics; D008223:Lymphoma / Q000503:physiopathology*; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D011496:Protein Methyltransferases / Q000378:metabolism; D011484:Protein-Arginine N-Methyltransferases; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012322:RNA Precursors / Q000378:metabolism*; D012326:RNA Splicing / Q000502:physiology*
chemical_list: D016376:Oligonucleotides, Antisense; D016271:Proto-Oncogene Proteins c-myc; D012322:RNA Precursors; D011496:Protein Methyltransferases; C498518:Prmt5 protein, mouse; D011484:Protein-Arginine N-Methyltransferases