Nonsense-mediated decay
[3] NMD was discovered when it was realized that cells often contain unexpectedly low concentrations of mRNAs that are transcribed from alleles carrying nonsense mutations.
In mammals, UPF2 and UPF3 are part of the exon-exon junction complex (EJC) bound to mRNA after splicing along with other proteins, eIF4AIII, MLN51, and the Y14/MAGOH heterodimer, which also function in NMD.
A popular model for the detection of aberrant transcripts in mammals suggests that during the first round of translation, the ribosome removes the exon-exon junction complexes bound to the mRNA after splicing occurs.
In both yeast and human cells, the major pathway for mRNA decay is initiated by the removal of the 5’ cap followed by degradation by XRN1, an exoribonuclease enzyme.
[9] These messages are predicted to be NMD-targets yet they (e.g., activity-regulated cytoskeleton-associated protein, known as Arc) can play crucial biologic functions suggesting that NMD may have physiologically relevant roles.
Comprehensive analyses large scale genetics and gene expression datasets have enabled the systemic identification of the complex rules governing NMD efficiency, and quantification of their relative importance and effect size.
[10] This revealed that the efficiency of NMD in recognizing and degrading these faulty transcripts is influenced by several molecular features: Although nonsense-mediated mRNA decay reduces nonsense codons, mutations can occur that lead to various health problems and diseases in humans.
Instead of decreased mRNA levels, a mutant transcript produces truncated β chains, which in turn leads to a clinical phenotype in the heterozygote.
This modulation of immunogenicity means that frameshift-derived neoantigens only contribute to the response to immune checkpoint inhibition if they arise from mutations in parts of the genome that are not recognized by NMD.
[citation needed] These peptides then interact with different melanocortin receptors (MCRs) and are involved in a wide range of processes including the regulation of body weight (MC3R and MC4R), adrenal steroidogenesis (MC2R) and hair pigmentation (MC1R).
The results from this experiment strongly suggest that the absence of red hair in non-European patients with early onset obesity and hormone deficiency does not exclude the occurrence of POMC mutations.
[14] By sequencing the patients DNA they found that this novel mutation has a collection of symptoms because of a malfunctioning nonsense-mediated mRNA decay surveillance pathway.
However, if the PTCs are in regions that evade NMD, the mutant mRNAs may be translated into truncated proteins, potentially retaining partial function and leading to incomplete gene inactivation.
[13][17] Therefore, understanding and incorporating NMD rules into the design of single guide RNAs (sgRNAs) is essential for achieving desired outcomes in CRISPR-Cas9 experiments.
Tools such as NMDetective[13] can predict the likelihood of NMD triggering based on the location of PTCs, thereby aiding in the design of more effective gene-editing strategies.
