MYC regulates the core pre-mRNA splicing machinery as an essential step in lymphomagenesis

The critical effectors of MYC overexpression during lymphomagenesis in transgenic mice are defined. MYC control of splicing machinery The MYC transcription factor is overexpressed in most human cancers and perturbs the expression of many genes. Here, Ernesto Guccione and colleagues define critical effectors of MYC overexpression during lymphomagenesis in transgenic mice. They find MYC directly regulates the core splicing machinery, including Sm proteins and the arginine methyltransferase PRMT5. These findings, together with previous genome-wide mapping of MYC binding and gene regulation, indicate that MYC is a master regulator of the core snRNP (small nuclear ribonucleic protein) machinery, ensuring proper mRNA splicing. Coordinated regulation of splicing fidelity by MYC is critical for cell survival and proliferation and suggests therapeutic strategies for MYC-driven tumours. Deregulated expression of the MYC transcription factor occurs in most human cancers and correlates with high proliferation, reprogrammed cellular metabolism and poor prognosis 1 . Overexpressed MYC binds to virtually all active promoters within a cell, although with different binding affinities 2 , 3 , 4 , and modulates the expression of distinct subsets of genes 1 , 2 , 4 , 5 . 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 6 , 7 . 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 2 , 3 , 4 , 5 and translation 8 , MYC also safeguards proper pre-messenger-RNA splicing as an essent