GIGA-Molecular Biology of Diseases, Gene Expression and Cancer Laboratory, B34 +1, University of Liege, Avenue de l'Hôpital 1, B-4000, Liège, Belgium.
CNRS, Institut de Génétique et Développement de Rennes (IGDR) UMR 6290, Université de Rennes, F-35043, Rennes, France.
Nat Commun. 2021 Nov 17;12(1):6648. doi: 10.1038/s41467-021-26932-2.
The U6 snRNA, the core catalytic component of the spliceosome, is extensively modified post-transcriptionally, with 2'-O-methylation being most common. However, how U6 2'-O-methylation is regulated remains largely unknown. Here we report that TFIP11, the human homolog of the yeast spliceosome disassembly factor Ntr1, localizes to nucleoli and Cajal Bodies and is essential for the 2'-O-methylation of U6. Mechanistically, we demonstrate that TFIP11 knockdown reduces the association of U6 snRNA with fibrillarin and associated snoRNAs, therefore altering U6 2'-O-methylation. We show U6 snRNA hypomethylation is associated with changes in assembly of the U4/U6.U5 tri-snRNP leading to defects in spliceosome assembly and alterations in splicing fidelity. Strikingly, this function of TFIP11 is independent of the RNA helicase DHX15, its known partner in yeast. In sum, our study demonstrates an unrecognized function for TFIP11 in U6 snRNP modification and U4/U6.U5 tri-snRNP assembly, identifying TFIP11 as a critical spliceosome assembly regulator.
U6 snRNA 是剪接体的核心催化成分，其在转录后被广泛修饰，最常见的是 2'-O-甲基化。然而，U6 的 2'-O-甲基化如何被调控仍知之甚少。在这里，我们报告人类 Ntr1 剪接体解体因子的同源物 TFIP11 定位于核仁及 Cajal 体，并对 U6 的 2'-O-甲基化至关重要。从机制上讲，我们证明 TFIP11 敲低会减少 U6 snRNA 与核仁纤维蛋白和相关 snoRNA 的结合，从而改变 U6 的 2'-O-甲基化。我们发现 U6 snRNA 的低甲基化与 U4/U6.U5 三 snRNP 的组装变化有关，导致剪接体组装缺陷和剪接保真度改变。引人注目的是，TFIP11 的这一功能与其在酵母中的已知伙伴 RNA 解旋酶 DHX15 无关。总之，我们的研究表明 TFIP11 在 U6 snRNP 修饰和 U4/U6.U5 三 snRNP 组装中具有未被认识的功能，确定 TFIP11 为关键的剪接体组装调控因子。
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