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.

Splicing-factor alterations in cancers

“…Interestingly, MYC appears to alter splicing by somewhat different mechanisms in lymphomagenesis versus breast cancer. In the former context, MYC hyperactivation affects the levels of specific splicing regulators (Koh et al 2015), whereas in the latter context, it promotes a global increase in pre-mRNA levels (Hsu et al 2015), although upregulation of particular splicing regulators was also previously reported Anczukow et al 2012;Das et al 2012). These ostensibly different findings suggest that many of the splicing changes associated with cancer are contextdependent.…”

“…As MYC is the most frequently amplified oncogene in human cancers and plays a crucial role in transformation, therapies that exploit the spliceosome would be very attractive. Both studies uncovered an essential role of the splicing machinery in MYC-driven transformation, and identified multiple associated abnormal splicing events, including intron retention (Hsu et al 2015;Koh et al 2015). Interestingly, MYC appears to alter splicing by somewhat different mechanisms in lymphomagenesis versus breast cancer.…”

“…Furthermore, SRSF1 not only contributes to MYC's oncogenic activity , but also cooperates with MYC in transformation, promoting the formation of more aggressive breast tumors (Anczukow et al 2012). In addition, two recent studies revealed that components of the spliceosome, such as PRMT5 and BUD31, are essential for MYC to function as an oncogene in lymphoma and breast cancer, respectively (Hsu et al 2015;Koh et al 2015). As MYC is the most frequently amplified oncogene in human cancers and plays a crucial role in transformation, therapies that exploit the spliceosome would be very attractive.…”

Unmasking the U2AF homology motif family: a bona fide protein–protein interaction motif in disguise

“…Despite many exposés, whether new confessions of ULM extensions, phosphorylation-sensitivity, and cooperative binding will emerge as recurring dramas among UHM-ULM partners for now remain tantalizing family secrets. In the longer term, understanding the interplay among UHMs and ULMs may offer new therapeutic avenues for targeting the spliceosome (for review, see Bonnal et al 2012), which has been highlighted recently for MYCdriven malignancies (Hirsch et al 2015;Hsu et al 2015;Koh et al 2015) and already is promising for compounds that target the ULM-containing protein SF3b155 (for review, see Salton and Misteli 2016).…”

Epigenomic reprogramming in inorganic arsenic-mediated gene expression patterns during carcinogenesis

“…The role of SRSF1 in carcinogenesis is well studied (150), and its expression is upregulated by MYC (151), which in itself is deregulated in iAs exposure (34,152). MYC also directly upregulates core pre-mRNA machinery during carcinogenesis and maintains appropriate splicing of alternative exons (153).…”