Functional inhibition of core spliceosomal machinery activates intronic premature cleavage and polyadenylation of pre-mRNAs.

IF 6.9 1区生物学 Q1 CELL BIOLOGY Cell reports Pub Date : 2025-03-25 Epub Date: 2025-02-27 DOI:10.1016/j.celrep.2025.115376

Qiumin Feng, Zejin Lin, Danhui Zhao, Mengzhao Li, Sheng Yang, Andy Peng Xiang, Congting Ye, Chengguo Yao

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Abstract

The catalytic role of U6 snRNP in pre-mRNA splicing has been well established. In this study, we utilize an antisense morpholino oligonucleotide (AMO) specifically targeting catalytic sites of U6 snRNA to achieve functional knockdown of U6 snRNP in HeLa cells. The data show a significant increase in global intronic premature cleavage and polyadenylation (PCPA) events, similar to those observed with U1 AMO treatment, as demonstrated by mRNA 3'-seq analysis. Mechanistically, we provide evidence that U6 AMO-mediated splicing inhibition might be the driving force for PCPA as application of another specific AMO targeting U2 snRNP results in similar global PCPA effects. Together with our recently published findings that demonstrate the global inhibitory effect of U4 snRNP on intronic PCPA, our data highlight the critical role of splicing in suppressing intronic PCPA and support a model in which splicing and polyadenylation may compete with each other within introns during co-transcriptional mRNA processing.

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核心剪接体机制的功能抑制激活内含子过早切割和前mrna的聚腺苷化。

U6 snRNP在pre-mRNA剪接中的催化作用已经得到了很好的证实。在本研究中，我们利用一种特异性靶向U6 snRNA催化位点的反义morpholino oligonucleotide （AMO）在HeLa细胞中实现了U6 snRNP的功能性敲低。mRNA 3'-seq分析显示，与U1 AMO处理相似，数据显示全局内含子过早切割和聚腺苷酸化（PCPA）事件显著增加。在机制上，我们提供的证据表明，U6 AMO介导的剪接抑制可能是PCPA的驱动力，因为应用另一种针对U2 snRNP的特定AMO会产生类似的全局PCPA效应。我们最近发表的研究结果表明，U4 snRNP对内含子PCPA具有全局抑制作用，我们的数据强调了剪接在抑制内含子PCPA中的关键作用，并支持了一个模型，即在共转录mRNA加工过程中，剪接和聚腺苷化可能在内含子内相互竞争。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.