Abstract
An estimated one-third of genetic disorders are the result of mutations that generate premature termination codons (PTCs) within protein coding genes. These disorders are phenotypically diverse and consist of diseases that affect both young and old individuals. Various small molecules have been identified that are capable of modulating the efficiency of translation termination, including select antibiotics of the aminoglycoside family and multiple novel synthetic molecules, including PTC124. Several of these agents have proved their effectiveness at promoting nonsense suppression in preclinical animal models, as well as in clinical trials. In addition, it has recently been shown that box H/ACA RNA-guided peudouridylation, when directed to modify PTCs, can also promote nonsense suppression. In this review, we summarize our current understanding of eukaryotic translation termination and discuss various methods for promoting the read-through of disease-causing PTCs, as well as the current obstacles that stand in the way of using the discussed agents broadly in clinical practice.
Highlights
KARIJOLICH and YU: THERAPEUTIC SUPPRESSION OF premature termination codons (PTCs): MECHANISMS AND CLINICAL CONSIDERATIONS to the C-terminally truncated protein that is synthesized as a result of the PTC, the presence of a PTC within a messenger RNA is often, though not always, accompanied with an increased rate of mRNA decay via nonsense mediated mRNA decay (NMD) [8]
Translation termination is mediated by eukaryotic release factor 1, which is responsible for stop codon recognition and triggering peptide release, and eRF3, a GTPase that stimulates eRF1-mediated peptide release [10,11]. eRF1, in turn, stabilizes binding of GTP to eRF3 so that they form a stable ternary complex [12,13] (Fig. 1)
A stop codon is not required for GTPase stimulation. eRF1 and eRF3 bind to ribosomal pre-termination complexes as an eRF1eRF3GTP ternary complex with peptide release being dependent on eRF3-mediated GTP hydrolysis [34]
Summary
Translation termination occurs when a stop codon enters the ribosomal A-site. For simplicity, termination can be thought of as two distinct steps, stop codon recognition and peptide release. ERF1, responsible for stop codon recognition, adopts a fold resembling that of a tRNA and is comprised of three distinct domains, namely N-terminal (N), middle (M) and C-terminal (C) [16]. Upon stop codon recognition the highly conserved Gly-Gly-Gln (GGQ) motif of eRF1, located within the M domain, is positioned within the peptidyl transferase center resulting in a rearrangement of rRNA, allowing for the entry of a water molecule and subsequent triggering of peptidyl-tRNA hydrolysis [27,28,29,30]. GTP hydrolysis releases eRF1's M domain from eRF3 enabling the correct positioning of the GGQ motif within the peptidyl transferase center, thereby promoting peptide hydrolysis [16]
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