近日，奥地利分子病理研究所Clemens Plaschka等研究人员合作解析剪接体分解的启动机制。相关论文于2024年6月26日在线发表在《自然》杂志上。

研究人员报告了线虫和人类末端内含子片段剪接体的2.6至3.2 Å分辨率冷冻电子显微镜结构以及生化和遗传数据。研究结果揭示了四种分解因子和保守的RNA螺旋酶DHX15如何启动剪接体的分解。分解因子探测剪接体的内外大表面，以检测连接的mRNA的释放。

然后，其中的两个因子（TFIP11和C19L1）和三个通用剪接体亚基（SYF1、SYF2和SDE2）对接并激活催化U6 snRNA上的DHX15，从而启动分解。这样，U6就控制了前体mRNA剪接的开始和结束。

综上所述，这些研究结果解释了典型剪接体分解的分子基础，并为理解通用剪接体RNA螺旋酶控制和异常剪接体的抛弃提供了一个框架。

研究人员表示，mRNA前体的剪接需要被称为剪接体的多兆道尔顿核糖核蛋白复合物的组装、重塑和分解。最近的研究揭示了剪接体的组装和重塑催化作用，但其分解机制仍不清楚。

附：英文原文

Title: Mechanism for the initiation of spliceosome disassembly

Author: Vorlnder, Matthias K., Rothe, Patricia, Kleifeld, Justus, Cormack, Eric, Veleti, Lalitha, Riabov-Bassat, Daria, Fin, Laura, Phillips, Alex W., Cochella, Luisa, Plaschka, Clemens

Issue&Volume: 2024-06-26

Abstract: Pre-mRNA splicing requires the assembly, remodeling, and disassembly of the multi-megadalton ribonucleoprotein complex called the spliceosome1. Recent studies have shed light on spliceosome assembly and remodeling for catalysis2–6, but the mechanism of disassembly remains unclear. Here, we report 2.6 to 3.2 resolution cryo-electron microscopy structures of nematode and human terminal intron-lariat spliceosomes along with biochemical and genetic data. Our results uncover how four disassembly factors and the conserved RNA helicase DHX15 initiate spliceosome disassembly. The disassembly factors probe large inner and outer spliceosome surfaces to detect the release of ligated mRNA. Two of these factors, TFIP11 and C19L1, and three general spliceosome subunits, SYF1, SYF2 and SDE2, then dock and activate DHX15 on the catalytic U6 snRNA to initiate disassembly. U6 thus controls both the start5 and end of pre-mRNA splicing. Taken together, our results explain the molecular basis of canonical spliceosome disassembly and provide a framework to understand general spliceosomal RNA helicase control and the discard of aberrant spliceosomes.

DOI: 10.1038/s41586-024-07741-1

Source: https://www.nature.com/articles/s41586-024-07741-1