What is the molecular function of MOV10 ATPase in RNA-induced silencing of mRNA?

描述（由申请人提供）：RNA诱导的沉默途径通过诱导靶mRNA的翻译抑制和/或激活降解来调节基因表达。在包括癌症在内的人类疾病中，越来越多地观察到该途径的畸变，如被称为oncomir的致癌miRNA的发现所代表的。这种途径需要一个约22 nt的小RNA分子（称为微（mi）RNA）来引导RNA诱导的沉默复合物（RISC）靶向mRNA。然而，沉默途径进展所需的许多因素尚未得到很好的理解，包括ATP酶MOV 10。M0 V10与含有miRNA的复合物相互作用，并且被认为是miRNA诱导的沉默所需的，然而，M0 V10的精确分子功能及其ATP酶活性仍然未被表征。此外，MOV 10是mRNP-重塑因子Upf 1的密切同源物，Upf 1重塑RNA-蛋白质复合物作为RNA加工事件（称为无义介导的衰变）的先决条件。我推测，MOV 10的行为类似于Upf 1在RNA诱导的沉默途径，以重塑RNA-蛋白质复合物，并促进这一途径的进展。本文提出的工作的目标是通过（1）确定MOV 10在RNA诱导的沉默中所需的步骤和（2）研究MOV 10的ATP酶结构域在内源性MOV 10靶点背景下的作用来理解MOV 10在mRNA沉默途径中的作用。MOV 10在人类细胞mRNA沉默中的重要性将通过分析MOV 10缺失对小RNA产生、RISC成熟、mRNP的翻译抑制和mRNA衰变的全局和生化影响来解决。接下来，将通过使用MOV 10的ATP酶突变体来研究MOV 10的ATP酶功能，以测试mRNP和miRNP的积累，假设MOV 10 ATP酶是重塑事件所需的。阐明MOV 10如何促进RNA诱导的沉默将增加我们对mRNA沉默的一般理解，并可能为mRNA沉默中的机械错误如何导致人类疾病提供新的见解。

DESCRIPTION (provided by applicant): The RNA-induced silencing pathway regulates gene expression by inducing translational repression and/or activating degradation of targeted mRNAs. Aberrations in this pathway are increasingly observed in human diseases, including cancer, as represented by the discovery of oncogenic miRNAs, known as oncomirs. This pathway requires a ~22nt small RNA molecule known as a micro (mi) RNA to guide the RNA-induced silencing complex (RISC) to the targeted mRNA. However, many of the factors that are required for the silencing pathway to progress are not well understood, including the ATPase MOV10. MOV10 interacts with miRNA-containing complexes and is believed to be required for miRNA- induced silencing, however, the precise molecular function of MOV10, and its ATPase activity, remain uncharacterized. Additionally, MOV10 is a close homolog of the mRNP-remodeling factor, Upf1, which remodels RNA-protein complexes as a prerequisite to the RNA-processing event known as nonsense mediated decay. I hypothesize that MOV10 acts analogously to Upf1 during the RNA-induced silencing pathway to remodel the RNA-protein complexes and facilitate progression of this pathway. The goal of the work proposed here is to understand the role of MOV10 in the mRNA silencing pathway by (1) determining the step(s) at which MOV10 is required in RNA-induced silencing and (2) investigating the role of the ATPase domain of MOV10 in the context of endogenous MOV10 targets. The importance of MOV10 in mRNA silencing in human cells will be addressed by analyzing the global and biochemical effects of MOV10 depletion on small RNA production, RISC maturation, translational repression of mRNPs, and mRNA decay. Next, the ATPase function of MOV10 will be studied by using ATPase mutants of MOV10 to test for accumulation of mRNPs and miRNPs with the hypothesis that MOV10 ATPase is required for a remodeling event. Elucidating how MOV10 facilitates RNA-induced silencing will add to our general understanding of mRNA silencing, and is likely to provide novel insights into how mechanistic errors in mRNA silencing may lead to human disease.