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Molecular Basis for mRNA Decay in Bacteria

细菌中 mRNA 衰变的分子基础

基本信息

批准号：
9030053
负责人：
Alexander Serganov
金额：
$ 33.48万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-21 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9030053
关键词：
Address Adopted Affect Affinity Bacteria Binding Biochemical Bioinformatics Biological Assay Biological Process Biology Catalysis Cell physiology Cells DNA Repair Data Dinucleoside Polyphosphates Diphosphates Enzymes Escherichia coli Excision Foundations Future Gene Expression Gene Expression Regulation Genetic Host Defense In Vitro Invaded Mammalian Cell Mediating Messenger RNA Metabolic Metabolism Methodology Methods Modeling Molecular Mutagenesis Organism Pathway interactions Personal Satisfaction Physiological Positioning Attribute Protein Biosynthesis Proteins RNA RNA Binding RNA Degradation RNA Sequences RNA triphosphatase Reaction Regulation Research Proposals Resistance Role Signal Transduction Specificity Stress Structure Substrate Specificity System Testing Time Transcript Translating Virulence X-Ray Crystallography base cellular targeting crosslink decapping enzyme design diadenosine tetraphosphate environmental change enzyme activity genome-wide in vitro activity in vivo inhibitor/antagonist inorganic phosphate insight mRNA Decay mRNA Transcript Degradation mRNA decapping member novel nudix hydrolase pathogen pathogenic bacteria protective effect public health relevance research study response transcriptome sequencing tripolyphosphate

项目摘要

DESCRIPTION (provided by applicant): A central problem in biology is to understand how cells optimize biological processes in response to changing environmental conditions. mRNA decay mechanisms contribute to coordination of activities by limiting the number of times each mRNA can be translated into protein molecules. Recent studies have identified a novel 5'-end-dependent mRNA decay pathway in bacteria triggered by the initial conversion of the triphosphorylated 5' end of primary transcripts to a monophosphate by the Nudix hydrolase RppH. A triphosphate on the 5'-end of bacterial mRNA has a protective effect analogous to that of the cap structure of eukaryotic mRNAs; therefore, pyrophosphate removal by RppH parallels the action of eukaryotic decapping enzymes. Despite its vital importance, 5'-end-dependent mRNA decay is among the least understood mechanisms of gene regulation. This proposal details a set of specific aims that address specificity, catalytic mechanism, and the role of RppH and RppH-associated factors in regulating gene expression in bacteria. The proposal integrates X-ray crystallography, genetics, biochemical methods, focused genome-wide RNA sequencing and bioinformatics. Specific Aim 1 is devoted to the determination of the catalytic mechanism of RppH and understanding the substrate specificity of RppH. This Aim will address molecular principles of RNA `decapping' based on the crystal structures of Escherichia coli RppH bound to model RNAs and structure-guided mutagenesis. Specific Aim 2 will validate a new model for the 5'-end-dependent mRNA decay. This Aim will identify and characterize new factors involved in the pathway and their impact on gene expression landscape. Specific Aim 3 will identify cellular mRNA targets of RppH on a genome-wide scale under various environmental conditions. This Aim will reveal the molecular features of RNAs that are important for RppH recognition and uncover the contribution of RppH to the control of gene expression in bacteria. The results of these studies will provide a comprehensive picture of the critical steps in the 5'-end-dependent pathway for bacterial mRNA decay and thereby address a fundamental gap in our understanding of the regulatory networks controlled by RNA degradation.