# Understanding the relationship between codon optimality and mRNA stability

> **NIH NIH R35** · JOHNS HOPKINS UNIVERSITY · 2024 · $608,823

## Abstract

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.

## Key facts

- **NIH application ID:** 10844508
- **Project number:** 5R35GM144114-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Jeffery Coller
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $608,823
- **Award type:** 5
- **Project period:** 2022-06-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10844508

## Citation

> US National Institutes of Health, RePORTER application 10844508, Understanding the relationship between codon optimality and mRNA stability (5R35GM144114-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10844508. Licensed CC0.

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