最近对真核转运 RNA 剪接核酸内切酶复合物的结构、功能和调控的见解,WIREs RNA

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最近对真核转运 RNA 剪接核酸内切酶复合物的结构、功能和调控的见解
WIREs RNA ( IF 6.4 ) Pub Date : 2022-02-14 , DOI: 10.1002/wrna.1717
Cassandra K. Hayne ₁ , Tanae A. Lewis ₂ , Robin E. Stanley ₁

Affiliation

对于含内含子的 tRNA，转移 RNA (tRNA) 内含子的剪接是 tRNA 成熟的关键步骤。在真核生物中，tRNA 剪接是一个多步骤过程，它依赖于几种 RNA 加工酶来促进内含子去除和外显子连接。剪接由 tRNA 剪接核酸内切酶 (TSEN) 复合物启动，该复合物通过其两个核酸酶亚基催化内含子的切除。TSEN 复合体的所有四个亚基中的突变都与称为脑桥小脑发育不全 (PCH) 的神经退行性和神经发育疾病家族有关。最近的研究为真核 TSEN 复合体的结构、功能和调控提供了分子见解，并开始阐明 TSEN 复合体中的突变如何导致神经退行性疾病。利用蛋白质结构预测的新进展，我们创建了人类 TSEN 复合体的三维模型。我们通过强调最近发现的真核 TSEN 复合物的底物来回顾 TSEN 复合物在 tRNA 剪接之外的功能，并讨论通过修饰切割的 tRNA 外显子和内含子的酶来调节 tRNA 剪接的机制。最后，我们回顾了最近的生化和动物模型，这些模型致力于解决驱动 PCH 的机制，并将这些研究与以前的研究相结合，以试图更好地了解 PCH 的发病机制。

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Recent insights into the structure, function, and regulation of the eukaryotic transfer RNA splicing endonuclease complex

The splicing of transfer RNA (tRNA) introns is a critical step of tRNA maturation, for intron-containing tRNAs. In eukaryotes, tRNA splicing is a multi-step process that relies on several RNA processing enzymes to facilitate intron removal and exon ligation. Splicing is initiated by the tRNA splicing endonuclease (TSEN) complex which catalyzes the excision of the intron through its two nuclease subunits. Mutations in all four subunits of the TSEN complex are linked to a family of neurodegenerative and neurodevelopmental diseases known as pontocerebellar hypoplasia (PCH). Recent studies provide molecular insights into the structure, function, and regulation of the eukaryotic TSEN complex and are beginning to illuminate how mutations in the TSEN complex lead to neurodegenerative disease. Using new advancements in the prediction of protein structure, we created a three-dimensional model of the human TSEN complex. We review functions of the TSEN complex beyond tRNA splicing by highlighting recently identified substrates of the eukaryotic TSEN complex and discuss mechanisms for the regulation of tRNA splicing, by enzymes that modify cleaved tRNA exons and introns. Finally, we review recent biochemical and animal models that have worked to address the mechanisms that drive PCH and synthesize these studies with previous studies to try to better understand PCH pathogenesis.

更新日期：2022-02-14

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