Nonsensemediated

Nonsense-mediated, most commonly referred to as nonsense-mediated decay (NMD), is a eukaryotic mRNA surveillance pathway that detects and degrades transcripts containing premature termination codons and certain other abnormalities. Its primary role is to prevent the production of truncated, potentially harmful proteins, but it also participates in regulating normal gene expression for a subset of transcripts.

In many organisms, NMD is triggered during or after a pioneer round of translation when a stop codon is encountered upstream of exon junction complexes (EJCs) remaining downstream of the termination site. Core factors include UPF1, UPF2, and UPF3 (UPF3X in vertebrates), with SMG1 kinase and downstream effectors SMG5, SMG6, and SMG7 coordinating the decay process. Depending on the context, the presence of an EJC downstream of a stop codon flags the transcript for decay, which can proceed via decapping, deadenylation, or endonucleolytic cleavage.

Triggers and scope: premature termination codons, long 3' untranslated regions, upstream open reading frames, and exon–junction complex composition influence sensitivity to NMD. While conserved across eukaryotes, the exact dependence on EJCs and mRNA architecture shows species-specific variation.

Clinical and research relevance: NMD affects the severity of genetic diseases caused by nonsense mutations by reducing mutant transcript levels. Therapeutic approaches sometimes aim to modulate NMD to preserve partially functional transcripts or to alter disease-related gene expression. NMD also intersects with alternative splicing and broader gene regulation, making it a significant factor in cellular transcriptomes.