Understanding the relationship between codon optimality and mRNA stability

了解密码子最优性和 mRNA 稳定性之间的关系

• 批准号: 10623162
• 负责人: Jeffery Coller
• 金额: $ 60.88万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10623162
• 关键词: 2019-nCoV; Accounting; Anticodon; Biological; Biology; Cell physiology; Cells; Chemicals; Codon Nucleotides; Complex; DNA; Development; Disparate; Equilibrium; Eukaryota; Event; Gene Expression Regulation; Genes; Genetic Code; Genetic Transcription; Influenza A Virus, H1N1 Subtype; Malignant Neoplasms; Messenger RNA; Modification; Molecular; Monitor; Movement; Pathway interactions; Prevalence; Process; Proteins; Regulation; Ribosomes; Speed; Thermodynamics; Transcriptional Regulation; Transfer RNA; Virus; Work; Yeasts; genetic information; mRNA Stability; mRNA Transcript Degradation; response; transmission process

Project Summary Messenger RNA transmits genetic information from DNA to protein. The regulation of mRNA levels is a fine balance between transcription rate and degradation rate. Transcriptional control is well documented and studied. Although the major pathways in mRNA turnover have been identified, accounting for disparate half-lives has been elusive. My lab has shown that codon optimality is a general feature that contributes greatly to mRNA stability in eukaryotes. Codon optimality reflects the disproportionate rate by which the ribosome deciphers each of the 61 codons. The randomness of tRNA selection during the mRNA decoding process manifests in codon optimality wherein tRNA concentrations/functionality dramatically influence rate. Accordingly, codon optimality is ultimately gauged by the relative prevalence of cognate tRNAs, wherein a codon is deemed `optimal' when tRNAs are in excess and conversely `non-optimal' when tRNAs are more limiting. Codon optimality is also determined by the thermodynamic stability of codon/anticodon pairing. Our major advance has been to show that the mRNA degradation machinery monitors ribosome speed and responds to degrade message when ribosome movement is relatively slow. In this proposal, we investigate how the mRNA degradation complex senses ribosome translocation rate as a function of codon optimality. We will determine the precise molecular events that occur in response to ribosome hesitations. Moreover, we focus on biological context where codon optimality is regulated both through mRNA chemical modification and tRNA regulated expression. Lastly the influence of codon optimality is now seen to be the major determinant of mRNA stability in yeast and in early development. Thus work through this project has uncovered a central and critical principle in biology that contributes broadly to gene expression regulation.

项目总结

项目成果

Codon optimality-mediated mRNA degradation: Linking translational elongation to mRNA stability.

• DOI: 10.1016/j.molcel.2022.03.032
• 发表时间: 2022-04-21
• 期刊: MOLECULAR CELL
• 影响因子: 16
• 作者: Bae, Haneui;Coller, Jeff
• 通讯作者: Coller, Jeff