Mechanisms of eIF3-mediated translation regulation

eIF3介导的翻译调控机制

• 批准号: 10469529
• 负责人: Amy Si-Ying Lee
• 金额: $ 44.5万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-16 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10469529
• 关键词: Address; Aging; Binding; Biochemical; Cell Differentiation process; Cell physiology; Cells; Complex; Congenital Disorders; Cues; Differentiation and Growth; Disease; Gene Expression; Gene Expression Regulation; Genes; Genetic Techniques; Genetic Translation; Malignant Neoplasms; Mediating; Methodology; Methods; Molecular; Peptide Initiation Factors; Phenotype; Process; Protein Biosynthesis; Proteins; RNA Binding; Regulation; Research; Ribosomal Proteins; Ribosomes; Role; Signal Transduction; System; Transcript; Translations; Work; base; cell growth; human disease; innovation; insight; novel; programs; rational design; response; scaffold; therapeutic target

Project Summary Exquisite spatial and temporal control of the proteins that are expressed in a cell is essential for correct differentiation and cell growth decisions. Despite being a central step in gene expression, how mRNA translation is regulated remains poorly understood. There is a gap in our understanding of the molecular basis of specialized translation of specific transcripts, and of the overall functional significance of this regulation on cellular responses to signaling cues. Here we propose to investigate the contribution of mRNA translation regulation to the dynamic gene expression programs that underlie cell physiology. The system we will focus on is the 13-subunit eIF3 translation initiation factor complex, which acts as a scaffold during general translation to organize interactions between the small ribosomal proteins and other initiation factors. We recently discovered that eIF3 can also control the translation of select cellular transcripts through novel RNA-binding and cap-binding activities. These findings demonstrate that canonical translation initiation factors moonlight in roles outside of general translation to drive expression of distinct gene programs. Despite these intriguing findings, and eIF3 being the largest component of the translation machinery besides the ribosome, ascribing functions to the majority of subunits has been challenging. Standard genetic techniques cannot be applied to eIF3; eIF3 subunits are essential for viability, and the assembly of the multi-subunit eIF3 complex is hindered by alterations to subunit levels. These methods also cannot segregate activities in general versus specialized translation. We will develop an innovative set of high-throughput methodologies to address these difficulties and comprehensively discover how eIF3 controls the dynamic gene programs during cell differentiation and cellular response to extrinsic signals. By combining these broad approaches with detailed biochemical and cell-based approaches, we will provide molecular understanding of the translation regulation networks that coordinate the precise control required for correct cellular function and signaling. This research will create new insights into fundamental principles of gene regulation. As eIF3 and other initiation factors are genetically associated with cancer, aging, congenital disorders, this work will also guide unconventional approaches to target translation regulation in disease.

项目摘要 在细胞中表达的蛋白质的精美空间和时间控制对于正确 分化和细胞生长决策。尽管是基因表达的核心步骤，但mRNA如何翻译 被监管仍然很熟悉。我们对专业分子基础的理解存在差距 特定转录本的翻译以及该调节对细胞反应的总体功能意义的翻译 发出信号提示。在这里，我们建议研究mRNA翻译调节对动态的贡献 基因表达程序是细胞生理的基础。我们将重点关注的系统是13-亚基EIF3 翻译起始因子复合物，在一般翻译过程中充当脚手架以组织相互作用 在小的核糖体蛋白和其他起始因子之间。我们最近发现EIF3也可以 通过新颖的RNA结合和盖结结合活动来控制精选细胞转录本的翻译。这些 调查结果表明，在一般翻译之外的角色中，典型的翻译起始因子月光月光下 推动不同基因程序的表达。尽管这些有趣的发现，而EIF3是最大的 除核糖体以外，翻译机械的组成部分，将功能归因于大多数亚基的功能 一直具有挑战性。标准遗传技术不能应用于EIF3； EIF3亚基对于 可行性和多亚基EIF3复合物的组装受到亚基水平的改变。这些 方法还不能以一般性和专业翻译中的方式分离活动。我们将发展创新 一组高通量方法，以解决这些困难，并全面发现EIF3 控制细胞分化和细胞对外部信号的细胞反应期间的动态基因程序。经过 将这些广泛的方法与详细的生化和基于细胞的方法相结合，我们将提供 分子理解翻译调节网络，以协调所需的精确控制 正确的蜂窝功能和信号传导。这项研究将为基因基因的基本原理提供新的见解 规定。由于EIF3和其他引发因素在遗传上与癌症，衰老，先天性疾病有关，因此 这项工作还将指导非常规的方法来靶向疾病的翻译调节。