Beyond codon optimality: codon pairs regulate mRNA stability dependent on translation
- 1Yale University
Abstract
The coding sequence of an mRNA directs its own decay, yet how codons, codon context, and amino acids collectively regulate mRNA stability remains poorly understood. Here we use a massively parallel reporter assay to decode this regulatory layer in zebrafish embryos. We find that codon pairs and amino acid pairs regulate mRNA stability beyond the level of individual codons. This regulation depends on the identity and order of neighboring codons and their encoded amino acids in a translation-dependent manner. The relative contributions of codon and amino acid combinations to mRNA stability can be quantified using machine learning. We further found that endogenous mRNAs are regulated by codon pairs, thereby governing developmental gene regulation and biological function. This codon context-dependent decay requires deadenylation and decapping by Cnot7 and Dcp2, with Upf1 acting on long non-optimal ORFs. Together, our results redefine codon optimality as a context-dependent, pair-level code with implications for RNA biology and therapeutic mRNA design.
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BibTeX
@misc{lee2026beyond,
title = {{Beyond codon optimality: codon pairs regulate mRNA stability dependent on translation}},
author = {H. Lee and D. Musaev and C. E. Vejnar and S. Krishna and T. D. Nguyen and E. C. Strayer and M. A. Messih and C. M. Takacs and J.-D. Beaudoin and A. J. Giraldez},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.15.751551},
url = {https://www.biorxiv.org/content/10.64898/2026.09.15.751551v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Beyond codon optimality: codon pairs regulate mRNA stability dependent on translation
AU - H. Lee
AU - D. Musaev
AU - C. E. Vejnar
AU - S. Krishna
AU - T. D. Nguyen
AU - E. C. Strayer
AU - M. A. Messih
AU - C. M. Takacs
AU - J.-D. Beaudoin
AU - A. J. Giraldez
PY - 2026
DA - 2026/09/15
PB - bioRxiv
DO - 10.64898/2026.09.15.751551
UR - https://www.biorxiv.org/content/10.64898/2026.09.15.751551v1
AB - The coding sequence of an mRNA directs its own decay, yet how codons, codon context, and amino acids collectively regulate mRNA stability remains poorly understood. Here we use a massively parallel reporter assay to decode this regulatory layer in zebrafish embryos. We find that codon pairs and amino acid pairs regulate mRNA stability beyond the level of individual codons. This regulation depends on the identity and order of neighboring codons and their encoded amino acids in a translation-dependent manner. The relative contributions of codon and amino acid combinations to mRNA stability can be quantified using machine learning. We further found that endogenous mRNAs are regulated by codon pairs, thereby governing developmental gene regulation and biological function. This codon context-dependent decay requires deadenylation and decapping by Cnot7 and Dcp2, with Upf1 acting on long non-optimal ORFs. Together, our results redefine codon optimality as a context-dependent, pair-level code with implications for RNA biology and therapeutic mRNA design.
ER -