Systematic Analysis of Nonsense Variants Uncovers Peptide Release Rate as a Novel Modifier of Nonsense-Mediated mRNA Decay

Authors

Divya Kolakada
Rui Fu
Nikita Biziaev
Alexey Shuvalov
Mlana Lore
Amy E Campbell
Michael A Cortázar
Marcin P Sajek
Jay R Hesselberth
Neelanjan Mukherjee
Elena Alkalaeva
Zeynep H Coban-Akdemir
Sujatha Jagannathan

Language

English

Publication Date

7-9-2025

Journal

Cell Genomics

DOI

10.1016/j.xgen.2025.100882

PMID

40393459

PMCID

PMC12278647

PubMedCentral® Posted Date

5-19-2025

PubMedCentral® Full Text Version

Post-print

Abstract

The phenotypic impact of nonsense variants is determined by nonsense-mediated mRNA decay (NMD), which degrades transcripts with premature termination codons (PTCs). Despite the clinical importance of nonsense variants, transcript-specific and context-dependent variations in NMD activity remain poorly understood. Here, we show that the amino acid preceding the PTC strongly influences NMD activity. Glycine codons promote robust NMD efficiency and show striking enrichment before PTCs but are depleted before normal termination codons. Glycine-PTC enrichment is particularly pronounced in genes tolerant to loss-of-function variants, suggesting efficient elimination of truncated proteins from nonessential genes. We further demonstrate that the peptide release rate during translation termination is an important determinant of NMD activity. We propose a "window of opportunity" model where translation termination kinetics modulate NMD activity. By revealing how sequence context shapes NMD activity through translation termination dynamics, our findings provide a mechanistic framework for improved clinical interpretation of nonsense variants.

Keywords

Nonsense Mediated mRNA Decay, Codon, Nonsense, Humans, RNA, Messenger, Peptides, Peptide Chain Termination, Translational, Codon, Terminator, NMD, PTC, translation, termination, splicing, loss-of-function, nonsense mutation

Published Open-Access

yes

Recommended Citation

Kolakada, Divya; Fu, Rui; Biziaev, Nikita; et al., "Systematic Analysis of Nonsense Variants Uncovers Peptide Release Rate as a Novel Modifier of Nonsense-Mediated mRNA Decay" (2025). Faculty, Staff and Student Publications. 5483.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5483