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Published on: September 27, 2015
Molecular Determinants and Therapeutic Targeting of Stop Codon Readthrough in Eukaryotic Translation
Wojciech Teodorowicz1, Oliver Mühlemann2
1Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
Abstract:
Accurate translation termination is essential for proteome integrity and in eukaryotes is primarily governed by the release factors eRF1 and eRF3, which ensure precise recognition of stop codons and efficient release of nascent polypeptides. However, proteome integrity is challenged by mutations that generate premature termination codons (PTCs), leading to truncated, nonfunctional proteins and degradation of the aberrant transcript via nonsense-mediated mRNA decay (NMD). Collectively, these events account for ∼1800 human genetic diseases. Translational readthrough, the process by which near-cognate tRNAs decode stop codons and allow ribosomes to continue elongation beyond the stop codon, represents a possibility to suppress PTCs and restore full-length protein synthesis. Initially discovered in viruses as a mechanism to expand coding capacity, readthrough is now recognized as a regulated feature of eukaryotic gene expression influenced by both cis-acting sequence elements and trans-acting factors. Recent evidence highlights the remarkable context dependence of readthrough, revealing variation across transcripts, tissues, and developmental stages. In this review, we examine the molecular determinants that define stop codon recognition and readthrough efficiency, with particular emphasis on nucleotide context. We further discuss the mechanisms and binding sites of small molecules that promote PTC readthrough, and summarize the clinical development landscape of readthrough-inducing compounds for the treatment of diseases caused by nonsense mutations.
Insights
Translational readthrough can suppress premature stop codons (PTCs) caused by genetic mutations, restoring full-length protein synthesis. This process, influenced by context, offers a therapeutic strategy for genetic diseases.
Area of Science:
- Molecular Biology
- Genetics
- Biochemistry
Background:
- Accurate translation termination is crucial for proteome integrity, involving release factors eRF1 and eRF3.
- Premature termination codons (PTCs) lead to truncated proteins and nonsense-mediated mRNA decay (NMD), causing numerous genetic diseases.
- Translational readthrough, decoding stop codons with near-cognate tRNAs, can bypass PTCs to restore protein synthesis.
Purpose of the Study:
- To review the molecular determinants of stop codon recognition and readthrough efficiency.
- To emphasize the role of nucleotide context in readthrough.
- To discuss small molecules that promote PTC readthrough and their clinical development for genetic diseases.
Main Methods:
- Examination of molecular mechanisms governing stop codon recognition.
- Analysis of cis-acting sequence elements and trans-acting factors influencing readthrough.
- Review of small molecule compounds that induce readthrough and their therapeutic potential.
Main Results:
- Readthrough efficiency is highly context-dependent, varying across transcripts, tissues, and developmental stages.
- Nucleotide context significantly impacts stop codon recognition and readthrough.
- Small molecules targeting PTC readthrough are under clinical development for genetic disorders.
Conclusions:
- Translational readthrough is a regulated biological process with therapeutic potential for genetic diseases caused by nonsense mutations.
- Understanding the molecular determinants of readthrough, particularly nucleotide context, is key to developing effective therapies.
- Readthrough-inducing compounds represent a promising therapeutic avenue for a range of genetic disorders.
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