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Nonsense-mediated mRNA Decay

Nonsense-mediated mRNA Decay

The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...

Translation

Translation

Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of Life
Proteins are...

Mutations

Mutations

Improving Translational Accuracy

Improving Translational Accuracy

Base complementarity between the three base pairs of mRNA codon and the tRNA anticodon is not a failsafe mechanism. Inaccuracies can range from a single mismatch to no correct base pairing at all. The free energy difference between the correct and nearly correct base pairs can be as small as 3 kcal/ mol. With complementarity being the only proofreading step, the estimated error frequency would be one wrong amino acid in every 100 amino acids incorporated. However, error frequencies observed in...

Leaky Scanning

Leaky Scanning

During most eukaryotic translation processes, the small 40S ribosome subunit scans an mRNA from its 5' end until it encounters the first start AUG codon. The large 60S ribosomal subunit then joins the smaller one to initiate protein synthesis. The location of the translation initiation is largely determined by the nucleotides near the start codon as there may be multiple translation initiation sites present on the mRNA. Marilyn Kozak discovered that the sequence RCCAUGG (where R...

Nuclear Export of mRNA

Nuclear Export of mRNA

Before mRNAs are exported to the cytoplasm, it is crucial to check each mRNA for structural and functional integrity. Eukaryotic cells use several different mechanisms, collectively known as mRNA surveillance, to look for irregularities in mRNAs. Irregular or aberrant mRNA are rapidly degraded by various enzymes. If a defective mRNA escapes the surveillance, it would be translated into a protein which would either be non-functional or not function properly. One of the primary irregularities in...

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Related Experiment Video

Updated: Aug 9, 2025

Measurement of Specific Mycobacterial Mistranslation Rates with Gain-of-function Reporter Systems

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Published on: April 26, 2019

Readthrough compounds for nonsense mutations: bridging the translational gap.

Sacha Spelier¹, Eveline P M van Doorn², Cornelis K van der Ent¹

¹Department of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, University Medical Center, Utrecht University, 3584, EA, Utrecht, The Netherlands; Regenerative Medicine Utrecht, University Medical Center, Utrecht University, 3584, CT, Utrecht, The Netherlands.

Trends in Molecular Medicine

|February 24, 2023

Summary

Nonsense mutations cause severe genetic diseases. While readthrough compounds show promise in preclinical studies, clinical results lag, indicating a gap between lab findings and patient treatments.

Keywords:

nonsense mutations nonsense-mediated decay rare diseases readthrough translational gap

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Last Updated: Aug 9, 2025

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Published on: April 26, 2019

In Vivo Modeling of the Morbid Human Genome using Danio rerio

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Area of Science:

Genetics
Molecular Biology
Pharmacology

Background:

Nonsense mutations account for ~10% of pathological mutations, leading to severe genetic diseases.
Current treatments for these diseases are limited.
Ribosomal readthrough of premature termination codons (PTCs) is a key strategy to restore full-length protein production.

Purpose of the Study:

To review preclinical and clinical research on compounds designed to enhance ribosomal readthrough.
To identify factors contributing to the translational gap between preclinical promise and clinical outcomes for readthrough compounds.

Main Methods:

Literature review of preclinical and clinical studies on readthrough-inducing compounds.
Analysis of factors influencing the efficacy and translation of these compounds.

Main Results:

Numerous compounds with readthrough potential have been identified over the last decade.
Preclinical data for these compounds are often promising.
Clinical studies have not yet demonstrated significant positive outcomes.

Conclusions:

A significant translational gap exists between preclinical efficacy and clinical success for readthrough compounds.
Further research is needed to understand and overcome the barriers limiting clinical translation for treating genetic diseases caused by nonsense mutations.