Letter

Deregulated expression of the MYC transcription factor occurs in most human cancers and correlates with high proliferation, repro-grammed cellular metabolism and poor prognosis 1 . Overexpressed MYC binds to virtually all active promoters within a cell, although with different binding affinities 2–4 , and modulates the expression of distinct subsets of genes 1,2,4,5 . However, the critical effectors of MYCin tumorigenesis remainlargely unknown. Herewe show that during lymphomagenesis in E m -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 9 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 E m -myc B cells. We conclude that, in addition