ArticleCell genomics2025
Systematic analysis of nonsense variants uncovers peptide release rate as a novel modifier of nonsense-mediated mRNA decay.
Article in Cell genomics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Uncovering the isoform-resolution kinetic landscape of nonsense-mediated mRNA decay with EZbakR.Genome biology · 2026Article
- Functional Characterization of a Novel Splice-Altering Intronic Variant in AMPD2 Associated with Pontocerebellar Hypoplasia Type 9.Cerebellum (London, England) · 2026Article
- Genomic stop codon scanning reveals quantitative principles of nonsense-mediated mRNA decay.bioRxiv : the preprint server for biology · 2025Article
- Integrative and accurate annotations enhance current nonsense-mediated mRNA decay rules.Nucleic acids research · 2025Article
- Identification of translation events that drive nonsense-mediated mRNA decay reveals functional roles for noncoding RNAs.bioRxiv : the preprint server for biology · 2025Article
- Stop codon context modulates NMD efficiency through translation termination kinetics.Cell genomics · 2025Article
- Mechanism-based approach in designing patient-specific combination therapies for nonsense mutation diseases.Nucleic acids research · 2025Article
- MultiplexedbioRxiv : the preprint server for biology · 2025Article
- Mechanism-based approach in designing patient-specific combination therapies for nonsense mutation diseases.bioRxiv : the preprint server for biology · 2024Article
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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.
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