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Dynamic interplay of eukaryotic translation and mRNA decay

真核翻译和 mRNA 衰减的动态相互作用

基本信息

批准号：
10884717
负责人：
Michael R Lawson
金额：
$ 24.9万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10884717
关键词：
ATP phosphohydrolase Affect Architecture Award Biological Assay Breast CRISPR screen Cryoelectron Microscopy Cystic Fibrosis Development Disease Duchenne muscular dystrophy Ensure Eukaryota Eukaryotic Cell Event Foundations Future Gene Expression Health Hereditary Neoplastic Syndromes Heritability Human In Vitro Individual Kinetics Language Learning Life Malignant Neoplasms Malignant neoplasm of ovary Mentors Messenger RNA Molecular Monitor Muscular Dystrophies Mutate Mutation Non-Stop Decay Nonsense Codon Open Reading Frames Outcome Pathway interactions Phase Postdoctoral Fellow Process Protein Biosynthesis Proteins Recycling Regulation Research Research Activity Ribosomes Signal Transduction Specificity Structural Biologist Structure System Techniques Terminator Codon Testing Therapeutic Time Training Training Activity Transcript Transfer RNA Translating Translations Work Yeasts genome-wide human disease inhibitor mRNA Decay novel therapeutics peptidyl-tRNA polypeptide premature programs reconstitution ribosome profiling single molecule skills time use translation factor

项目摘要

PROJECT SUMMARY / ABSTRACT Translation of eukaryotic mRNAs is highly regulated, and mutations that prematurely halt translation cause 11% of all heritable human diseases. Yet, it is unknown how ribosomes rapidly and accurately identify stop codons to halt protein synthesis and release the nascent polypeptide. It is also unclear how ribosomes trapped on an aberrant mRNA, such as those devoid of a stop codon, are liberated by decay machinery. An understanding of these fundamental processes could facilitate the discovery of novel therapeutics for diseases such as Cystic Fibrosis, Duchenne Muscular Dystrophy, and hereditary cancer syndromes. My central hypothesis is that the slow rate at which aberrant mRNAs are translated by ribosomes is exploited by slowly-acting decay factors to specifically degrade aberrant mRNAs and leave normal ones untouched. Examination of this hypothesis will require real-time tracking of ribosomes translating normal or aberrant mRNAs, capturing intricacies of pathway dynamics that are critical for regulation. As a postdoc in Joseph Puglisi’s lab at Stanford, I established single- molecule assays to directly track individual eukaryotic ribosomes throughout termination using an in vitro- reconstituted system. Co-mentored by Rachel Green, an expert in eukaryotic translation and mRNA decay, I will extend these assays to monitor other key events in termination, recycling, and mRNA decay. I will further assess the architecture of unique sub-states in translation and mRNA decay using cryo-EM. I propose the following specific aims: (I) Decipher the mechanisms that ensure fidelity in eukaryotic termination; (II) Define the dynamics that liberate ribosomes from normal and aberrant mRNAs; (III) Determine how termination, recycling, and mRNA decay are regulated in humans. Together, the proposed aims will reveal how eukaryotic cells distinguish between normal and aberrant mRNAs. Supported by my mentoring team, I will obtain expertise in cryo-EM, and the additional training necessary to expand beyond my initial studies of translational control into related mRNA decay mechanisms in yeast and humans. I will also become conversant in the language of genome-wide techniques such as CRISPR screening and ribosome profiling. The proposed research and training activities will provide me with the skills needed to establish an independent research program focused on the dynamic interplay of eukaryotic translation and mRNA decay, and reveal fundamental facets of gene expression with relevance to human health to be built upon in a future R01.

项目摘要/摘要