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

Deregulated expression of the MYC transcription factor occurs in most human cancers and correlates with high proliferation, reprogrammed cellular metabolism and poor prognosis1. Overexpressed MYC binds to virtually all active promoters within a cell, although with different binding affinities2-4, and modulates the expression of distinct subsets of genes1,2,4,5. However, the critical effectors of MYCin tumorigenesis remain largely unknown. Here we show that during lymphomagenesis in Em-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 proteins6,7. 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 59 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 Em-myc B cells. We conclude that, in addition to its well-documented oncogenic functions in transcription2-5 and translation8, MYC also safeguards proper pre-messenger-RNA splicing as an essential step in lymphomagenesis.