Understanding the interconnection between mRNA turnover and mRNA translation

了解 mRNA 周转和 mRNA 翻译之间的相互关系

• 批准号: 10177112
• 负责人: Jeffery Coller
• 金额: $ 36.84万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-10 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10177112
• 关键词: Accounting; Binding; Biological; Cells; Codon Nucleotides; Complex; Cryoelectron Microscopy; DNA; Data; Defect; Digestion; Embryonic Development; Enzymes; Eukaryota; Event; Excision; Exhibits; Failure; Gene Expression; Gene Expression Regulation; Genetic Code; Genetic Translation; Goals; Grant; Health; Human; Individual; Lead; Learning; Light; Malignant Neoplasms; Maps; Mediating; Messenger RNA; Mutation; Neurologic; Neurons; Output; Pathway interactions; Play; Poly(A) Tail; Process; Proteins; RNA; Recruitment Activity; Regulation; Ribosomes; Role; Saccharomycetales; Sense Codon; Signal Transduction; System; Testing; Transfer RNA; Translation Process; Translations; Work; Yeast Model System; Yeasts; base; crosslinking and immunoprecipitation sequencing; design; experimental study; genetic information; genome-wide; insight; mRNA Decay; mRNA Stability; mRNA Transcript Degradation; mRNA decapping; malformation; novel; protein function; recruit; response; sensor; spleen exonuclease; transcriptome; yeast two hybrid system

Abstract Messenger RNA (mRNA) decay is a critical step in the regulation of gene expression. mRNA decay in eukaryotes proceeds by removal of the 3' poly(A) tail (deadenylation) followed by removal of the 5' cap (decapping) then destruction of mRNA by 5' - 3' exonuclease digestion. This process of decay is intimately connected to mRNA translation, and a major goal of the field is to understand how translation interacts with decay to set decay rates. Our lab has made the important discovery that codon optimality is a critical determinant of decay rates transcriptome- wide. Further, we have identified the DEAD-box protein DHH1 as the sensor that detects slowed translation elongation associated with non-optimal codons and directs these messages to decapping and degradation. In light of this novel function for DHH1, this proposal seeks to understand the mechanism by which DHH1 senses slowed translation elongation and transmits this information to the decapping complex. The first aim is designed to understand how DHH1 interacts with the ribosome to sense slowed elongation. The second aim focuses on how DHH1 transmits a slowed elongation signal to the decapping complex. The third aim is to determine how deadenylation sensitizes mRNA to DHH1. Together, these aims will inform how DHH1 functions, thus providing insight into a wide range of gene expression events.

摘要

项目成果

Suppression of premature transcription termination leads to reduced mRNA isoform diversity and neurodegeneration.

• DOI: 10.1016/j.neuron.2022.01.018
• 发表时间: 2022-04-20
• 期刊: Neuron
• 影响因子: 16.2
• 作者: LaForce GR;Farr JS;Liu J;Akesson C;Gumus E;Pinkard O;Miranda HC;Johnson K;Sweet TJ;Ji P;Lin A;Coller J;Philippidou P;Wagner EJ;Schaffer AE
• 通讯作者: Schaffer AE

Attenuated Codon Optimality Contributes to Neural-Specific mRNA Decay in Drosophila.

• DOI: 10.1016/j.celrep.2018.07.039
• 发表时间: 2018-08-14
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Burow DA;Martin S;Quail JF;Alhusaini N;Coller J;Cleary MD
• 通讯作者: Cleary MD

Co-translational mRNA decay in Saccharomyces cerevisiae.

• DOI: 10.1038/nature08265
• 发表时间: 2009-09-10
• 期刊: Nature
• 影响因子: 64.8

Codon optimality is a major determinant of mRNA stability.

• DOI: 10.1016/j.cell.2015.02.029
• 发表时间: 2015-03-12
• 期刊: Cell
• 影响因子: 64.5
• 作者: Presnyak V;Alhusaini N;Chen YH;Martin S;Morris N;Kline N;Olson S;Weinberg D;Baker KE;Graveley BR;Coller J
• 通讯作者: Coller J

The Ccr4-Not complex monitors the translating ribosome for codon optimality.

• DOI: 10.1126/science.aay6912
• 发表时间: 2020-04-17
• 期刊: Science (New York, N.Y.)
• 作者: Buschauer R;Matsuo Y;Sugiyama T;Chen YH;Alhusaini N;Sweet T;Ikeuchi K;Cheng J;Matsuki Y;Nobuta R;Gilmozzi A;Berninghausen O;Tesina P;Becker T;Coller J;Inada T;Beckmann R
• 通讯作者: Beckmann R