Protein arginine methyltransferase 5 sustains Tip60-EP400 complex via SRSF1 in Merkel cell carcinoma.

Protein arginine methyltransferase 5 (PRMT5) is a key regulator of gene expression and RNA splicing, with therapeutic potential demonstrated in MTAP-deleted cancers. Emerging evidence suggests that MYC-driven tumors or tumors with wild-type TP53 may also be sensitive to PRMT5 inhibition, though the underlying mechanisms remain unclear. Virus-positive Merkel cell carcinoma serves as an ideal model to explore this, as it is driven by the MYC paralog MYCL and retains wild-type TP53 In this study, we examined how PRMT5 regulates the Tip60-EP400 complex, which is recruited by MYCL in Merkel cell carcinoma. Using RNA-seq, we characterized PRMT5-mediated gene expression, whereas Iso-Seq enabled in-depth analysis of PRMT5-mediated alternative splicing. How PRMT5 deficiency selectively affects certain splice sites remains unresolved. Our findings suggest that PRMT5-mediated modification of SRSF1 (serine/arginine-rich splicing factor 1) enhances its recruitment to m6A-modified RNA, ensuring proper KAT5 (Tip60) splicing and Tip60-EP400 activity. PRMT5 inhibition disrupts this recruitment, leading to widespread splicing defects, including exon skipping and intron retention. These results provide new insights into PRMT5's role in splicing regulation and may have broader implications for targeting splicing dysregulation in MYC-driven cancers.