Therapeutic suppression of premature termination codons: mechanisms and clinical considerations (review)

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.

Figure 1

Translation termination in eukaryotes. Eukaryotic release factor 1 (eRF1) and eRF3 bind to ribosomal pre-termination complexes as an eRF1•eRF3•GTP ternary complex. GTP hydrolysis facilitates the positioning of the GGQ motif of eRF1 into the peptidyl transferase center. eRF1 induces peptide release.

Figure 2

Structures of agents shown to possess nonsense suppressive properties.

Figure 3

Box H/ACA ribonucleoproteins (RNPs) catalyze pseudouridylation. (A) Pseudouridine is the 5-ribosyl isomer of uridine. Dashed arrow represents the rotational axis. (B) Box H/ACA RNPs consist of four core proteins, namely Dyskerin, Gar1, Nhp2 and Nop10. Dyskerin is the pseudouridine synthease. Cbf5 is the Dyskerin homologue in yeast.