Sevigny Joseph L, Proctor Evelyn V, Adams Heather, MacDonald Erin R, Thomas W Kelley, Cheng Jingwei
Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, NH, USA.
Hubbard Center for Genome Studies, University of New Hampshire, Durham, NH, USA.
Life Sci Alliance. 2025 Aug 22;8(11). doi: 10.26508/lsa.202503316. Print 2025 Nov.
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 -driven tumors or tumors with wild-type 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 paralog and retains wild-type 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 (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 -driven cancers.
蛋白质精氨酸甲基转移酶5（PRMT5）是基因表达和RNA剪接的关键调节因子，在MTAP缺失的癌症中显示出治疗潜力。新出现的证据表明，由[此处原文缺失相关基因名称]驱动的肿瘤或具有野生型[此处原文缺失相关基因名称]的肿瘤可能也对PRMT5抑制敏感，但其潜在机制仍不清楚。病毒阳性默克尔细胞癌是探索这一问题的理想模型，因为它由[此处原文缺失相关基因名称]旁系同源物驱动且保留野生型[此处原文缺失相关基因名称]。在本研究中，我们研究了PRMT5如何调节Tip60-EP400复合物，该复合物在默克尔细胞癌中由MYCL招募。使用RNA测序，我们对PRMT5介导的基因表达进行了表征，而Iso-Seq能够深入分析PRMT5介导的可变剪接。PRMT5缺乏如何选择性地影响某些剪接位点仍未得到解决。我们的研究结果表明，PRMT5介导的富含丝氨酸/精氨酸的剪接因子1（SRSF1）修饰增强了其对m6A修饰RNA的募集，确保了Tip60的正确剪接和Tip60-EP400活性。PRMT5抑制会破坏这种募集，导致广泛的剪接缺陷，包括外显子跳跃和内含子保留。这些结果为PRMT5在剪接调控中的作用提供了新的见解，可能对靶向[此处原文缺失相关基因名称]驱动的癌症中的剪接失调具有更广泛的意义。
