<br>GPATCH4 以 DHX15 依赖和 DHX15 独立方式调节 rRNA 和 snRNA 2′-O-甲基化,Nucleic Acids Research

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GPATCH4 以 DHX15 依赖和 DHX15 独立方式调节 rRNA 和 snRNA 2′-O-甲基化
Nucleic Acids Research ( IF 16.6 ) Pub Date : 2023-12-19 , DOI: 10.1093/nar/gkad1202
Nidhi Kanwal ₁ , Nicolai Krogh ₂ , Indira Memet ₁ , Nicolas Lemus-Diaz ₁ , Chairini C Thomé ₁ , Luisa M Welp _{3,

4} , Athanasia Mizi ₅ , Philipp Hackert ₁ , Argyris Papantonis ₅ , Henning Urlaub _{3,

4,

6,

7} , Henrik Nielsen ₂ , Katherine E Bohnsack _{1,

6} , Markus T Bohnsack _{1,

6,

7,

8}

Affiliation

RNA 解旋酶活性的调节通常由蛋白质辅因子完成，对于确保复杂细胞环境中的靶标特异性至关重要。 RNA 解旋酶辅助因子的最大家族是 G-patch 蛋白，但许多人类 G-patch 蛋白的同源 RNA 解旋酶和细胞功能仍然难以捉摸。在这里，我们发现 GPATCH4 是 DHX15 的刺激辅因子，通过其 G-patch 结构域中的残基与核仁中的 DEAH 盒解旋酶相互作用。我们发现 GPATCH4 与前核糖体颗粒相关，并与转录的核糖体 DNA 位点和前体核糖体 RNA 交联，并与指导 rRNA 和 snRNA 修饰的小核仁和小卡哈尔体相关 RNA 结合。 GPATCH4 的缺失会损害各个 rRNA 和 snRNA 位点的 2'-O-甲基化，导致蛋白质合成和细胞生长减少。我们证明 GPATCH4 对 2'-O-甲基化的调节既依赖于又独立于其与 DHX15 的相互作用。有趣的是，DHX15 的 ATPase 活性对于 DHX15 依赖性位点的有效甲基化是必需的，这表明 DHX15 在调节 snoRNA 引导的 rRNA 2'-O-甲基化中具有功能，需要 GPATCH4 激活。总体而言，我们的研究结果扩展了关于 G-patch 蛋白调节 RNA 解旋酶的知识，并为调节 rRNA 和 snRNA 修饰安装的机制提供了重要的新见解，这对于核糖体功能和前 mRNA 剪接至关重要。

"点击查看英文标题和摘要"

GPATCH4 regulates rRNA and snRNA 2′-O-methylation in both DHX15-dependent and DHX15-independent manners

Regulation of RNA helicase activity, often accomplished by protein cofactors, is essential to ensure target specificity within the complex cellular environment. The largest family of RNA helicase cofactors are the G-patch proteins, but the cognate RNA helicases and cellular functions of numerous human G-patch proteins remain elusive. Here, we discover that GPATCH4 is a stimulatory cofactor of DHX15 that interacts with the DEAH box helicase in the nucleolus via residues in its G-patch domain. We reveal that GPATCH4 associates with pre-ribosomal particles, and crosslinks to the transcribed ribosomal DNA locus and precursor ribosomal RNAs as well as binding to small nucleolar- and small Cajal body-associated RNAs that guide rRNA and snRNA modifications. Loss of GPATCH4 impairs 2′-O-methylation at various rRNA and snRNA sites leading to decreased protein synthesis and cell growth. We demonstrate that the regulation of 2′-O-methylation by GPATCH4 is both dependent on, and independent of, its interaction with DHX15. Intriguingly, the ATPase activity of DHX15 is necessary for efficient methylation of DHX15-dependent sites, suggesting a function of DHX15 in regulating snoRNA-guided 2′-O-methylation of rRNA that requires activation by GPATCH4. Overall, our findings extend knowledge on RNA helicase regulation by G-patch proteins and also provide important new insights into the mechanisms regulating installation of rRNA and snRNA modifications, which are essential for ribosome function and pre-mRNA splicing.

更新日期：2023-12-19

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