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Chemical Biology

Ignore the nonsense

A small molecule forces the protein-translation machinery to overlook the signals that would otherwise result in its premature termination. Genuine stop signs are, however, read and obeyed.

Several inherited diseases are caused by mutations in single nucleotides within genes. These mutations can transform the products of messenger RNA codons, the sets of three nucleotides that determine which amino acid is incorporated into the growing protein chain. When such 'nonsense' mutations are transcribed into a 'stop' codon, the cellular machinery that translates mRNA into protein misinterprets the codon as a signal to terminate protein synthesis. These false stop codons are known as premature termination codons (PTCs) and result in the formation of truncated proteins that cannot function properly and may even damage the cell, eventually leading to disease. Depending on the disorder, nonsense mutations account for 5–70% of cases of genetic disorders, including cystic fibrosis, muscular dystrophy and several types of cancer. On page 87 of this issue, Welch et al.1 report that a small organic molecule known as PTC124 can force the translation machinery to ignore PTCs, without preventing it from reading the real stop signalsFootnote 1.

It has been known for the past 10 years that the antibiotic gentamycin can prompt ribosomes — the core component of the cellular protein-synthesis machinery — to read through PTCs, thereby generating full-length proteins2. Nevertheless, the clinical benefit of gentamycin is limited, because to be effective it has to be used at very high concentrations, which are associated with severe side effects. There is now hope that PTC124, which, like gentamycin, ignores PTCs but lacks its adverse side effects, could be more beneficial in the clinic. Indeed, interim results of phase II clinical trials3 indicate that patients with PTC-induced forms of cystic fibrosis and Duchenne muscular dystrophy might benefit from treatment with PTC124 — a promising result that has been commented on for some time4,5.

Welch et al.1 describe an astonishing feature of PTC124 — its selectivity for PTCs. Why is this so striking? All organisms with membrane-bound cell nuclei (eukaryotes) have evolved mechanisms to protect themselves from the harmful products of nonsense mutations. There are two lines of defence. The first relies on the fast and efficient degradation of the truncated proteins after the translation of PTC-containing mRNAs. The second acts before these proteins are synthesized. This quality-control mechanism, known as nonsense-mediated mRNA decay (NMD), detects and degrades PTC-containing mRNAs6. But how is a PTC distinguished from a normal termination codon? The answer came from the discovery that, in all organisms, NMD requires ongoing protein translation.

The only cellular entity that can read the genetic code, and so decipher stop codons, is the ribosome. In mammals, PTC recognition occurs during an initial 'pioneer' round of translation in which — unlike 'productive' translation, which results in protein synthesis — a ribosome scans only newly synthesized mRNAs for the presence of PTCs7. NMD is closely linked to mRNA splicing — a process in which non-coding sequences of a gene (introns), which have been transcribed into the precursor mRNA, are removed. After re-joining of the coding sequences (exons), the splicing machinery labels the joining sites by attaching a set of proteins known collectively as the exon-junction complex. As a rule, the ribosome identifies a termination codon as premature if it is more than 55 bases upstream of an exon-junction complex8.

Although NMD's role in mRNA quality control has been known for many years, recent observations indicate that this might not be its main function. On inactivation of the NMD machinery, about 10% of the transcriptome — the set of all mRNAs in a cell — of yeast and human cells are differentially expressed, indicating that NMD is involved in the regulation of gene expression9,10,11. Examples of NMD-regulated molecules include several proteins that are involved in amino-acid synthesis, as well as pseudo-genes that do not encode a protein but are the source of non-coding RNAs such as small nucleolar RNAs12.

Therefore, drug-induced readthrough of PTCs could enhance protein expression in two ways. First, by directly suppressing premature termination during the productive translation of mRNA, it could increase the efficiency of translation (Fig. 1a). Second, by suppressing PTC recognition during pioneer translation, it could prevent NMD, thereby increasing the number of mRNA sequences that are available for productive translation (Fig. 1b). Although both possibilities lead to a favourable increase in protein translation, the second is associated with a risk of an increased amount of mutated proteins and mRNAs, which are normally absent because of mRNA degradation by NMD.

Figure 1: Possible mechanisms of PTC124-enhanced translation.
figure1

a, PTC124 could directly suppress termination of 'productive' protein translation at a premature termination codon (PTC), leading to increased levels of functional full-length proteins. b, Alternatively, PTC124 might suppress the identification of PTCs in 'pioneer' translation, thereby preventing nonsense-mediated mRNA decay (NMD), which is induced if a ribosome hits a stop codon more than 55 bases upstream of an exon-junction complex (EJC). This would lead to the stabilization of PTC-containing mRNAs, allowing their translation, presumably through the mechanism shown in a. The work of Welch et al.1 supports the model depicted in a.

Welch et al.1 found that, fortunately, PTC124 seems to selectively target productively translating ribosomes, and does not interfere with those that are engaged in NMD. In this way, PTC124 differs from gentamycin, which induces upregulation of several mRNAs that are known to be NMD substrates.

As well as being a prerequisite for its therapeutic efficacy, the specificity of PTC124 could be a starting point for a better understanding of the differences between the productive and the pioneer modes of translation. Although other distinct agents (besides ribosomes) are required for these two types of translation, we don't have detailed structural and functional information about them. The identification of the molecular target of PTC124 should help to fill this gap. Thus, in addition to being a promising drug, PTC124 may also become a research tool for elucidating the underlying mechanisms of the termination of protein translation.

Notes

  1. 1.

    This article and the paper concerned1 were published online on 22 April 2007.

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Schmitz, A., Famulok, M. Ignore the nonsense. Nature 447, 42–43 (2007). https://doi.org/10.1038/nature05715

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