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

描述（由申请人提供）：rna诱导沉默途径通过诱导翻译抑制和/或激活靶向mrna的降解来调节基因表达。在包括癌症在内的人类疾病中，越来越多地观察到这一途径的畸变，以致癌mirna（称为oncomir）的发现为代表。这一途径需要一种约22nt的小RNA分子，称为微RNA (mi)，来引导RNA诱导沉默复合体（RISC）到达目标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MOV10。MOV10与含有miRNA的复合物相互作用，被认为是miRNA诱导的沉默所必需的，然而，MOV10的确切分子功能及其atp酶活性尚不清楚。此外，MOV10是mrnp重塑因子Upf1的同源物，Upf1重塑rna -蛋白复合物，作为rna加工事件的先决条件，被称为无义介导的衰变。我假设MOV10在rna诱导的沉默途径中类似于Upf1，以重塑rna -蛋白复合物并促进该途径的进展。本文提出的工作目标是通过(1)确定在rna诱导的沉默中需要MOV10的步骤(s)和(2)研究MOV10的ATPase结构域在内源性MOV10靶点背景下的作用来了解MOV10在mRNA沉默途径中的作用。通过分析MOV10缺失对小RNA产生、RISC成熟、mRNPs的翻译抑制和mRNA衰变的全局和生化影响，我们将阐述MOV10在人类细胞mRNA沉默中的重要性。接下来，我们将利用MOV10的ATPase突变体来研究MOV10的ATPase功能，并假设重塑事件需要MOV10的ATPase，以检测mRNPs和miRNPs的积累。阐明MOV10如何促进rna诱导的沉默将增加我们对mRNA沉默的总体理解，并可能为mRNA沉默的机制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.