Aminoglycoside-mediated promotion of translation readthrough occurs through a non-stochastic mechanism that competes with translation termination

Chowdhury, Hasnin M.; Siddiqui, Aarif; Kanneganti, Seshu K.; Sharmin, Nahid; Chowdhury, M.; Nasim, Talat

doi:10.1093/hmg/ddx409

Cited by 22 publications

(20 citation statements)

References 43 publications

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“…Aminoglycoside antibiotics have long been suggested as a way to promote PTC recognition by near cognate tRNA, essentially competing with translation termination [ 49 ] and enabling the synthesis of a full-length protein [ 50 , 51 ]. Despite initial concerns with toxicity and side effects, these molecules have shown some success in clinical trials.…”

Section: Suppression Of Nonsense Mutations: Approaches and Challenmentioning

confidence: 99%

Suppression of Nonsense Mutations by New Emerging Technologies

Morais

Adachi

2020

IJMS

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Nonsense mutations often result from single nucleotide substitutions that change a sense codon (coding for an amino acid) to a nonsense or premature termination codon (PTC) within the coding region of a gene. The impact of nonsense mutations is two-fold: (1) the PTC-containing mRNA is degraded by a surveillance pathway called nonsense-mediated mRNA decay (NMD) and (2) protein translation stops prematurely at the PTC codon, and thus no functional full-length protein is produced. As such, nonsense mutations result in a large number of human diseases. Nonsense suppression is a strategy that aims to correct the defects of hundreds of genetic disorders and reverse disease phenotypes and conditions. While most clinical trials have been performed with small molecules, there is an increasing need for sequence-specific repair approaches that are safer and adaptable to personalized medicine. Here, we discuss recent advances in both conventional strategies as well as new technologies. Several of these will soon be tested in clinical trials as nonsense therapies, even if they still have some limitations and challenges to overcome.

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Section: Suppression Of Nonsense Mutations: Approaches and Challenmentioning

confidence: 99%

Suppression of Nonsense Mutations by New Emerging Technologies

Morais

Adachi

2020

IJMS

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“…Amlexanox, Ataluren, RTC13 and G418 have proven to be effective in read-through induction in several different PTCs both in vitro and in vivo (Gonzalez-Hilarion et al, 2012;Howard et al, 1996;Heier and DiDonato, 2009;Floquet et al, 2011;Salvatori et al, 2009;Brasell et al, 2019;Yu et al, 2014;Tan et al, 2011;Wilschanski et al, 2011;Du et al, 2008;Sánchez-Alcudia et al, 2012;Schwarz et al, 2015;Martorell et al, 2019). However, it is also important to mention that some criticism has been raised against Ataluren, its mode of action and its ability to induce PTC read-through (Chowdhury et al, 2018;McElroy et al, 2013;Auld et al, 2009;Dranchak et al, 2011). Adequate dosage and incubation time may be factors for each of the tested compounds, but our choice of both relied on past published readthrough induction in various in vitro/vivo conditions (Gonzalez-Hilarion et al, 2012;Lentini et al, 2014;Heier and DiDonato, 2009;Tan et al, 2011;Sánchez-Alcudia et al, 2012;Dranchak et al, 2011;Gómez-Grau et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Absence of p.R50X Pygm read-through in McArdle disease cellular models

Tarrasó

Real-Martinez

Parés

et al. 2020

Disease Models &Amp; Mechanisms

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McArdle disease is an autosomal recessive disorder caused by the absence of muscle glycogen phosphorylase, which leads to blocked muscle glycogen breakdown. We used three different cellular models to evaluate the efficiency of different read-through agents (including amlexanox, Ataluren, RTC13 and G418) in McArdle disease. The first model consisted of HeLa cells transfected with two different GFP-PYGM constructs presenting the Pygm p.R50X mutation (GFP-PYGM p.R50X and PYGM Ex1-GFP p.R50X). The second cellular model was based on the creation of HEK293T cell lines stably expressing the PYGM Ex1-GFP p.R50X construct. As these plasmids encode murine Pygm cDNA without any intron sequence, their transfection in cells would allow for analysis of the efficacy of readthrough agents with no concomitant nonsense-mediated decay interference. The third model consisted of skeletal muscle cultures derived from the McArdle mouse model (knock-in for the p.R50X mutation in the Pygm gene). We found no evidence of read-through at detectable levels in any of the models evaluated. We performed a literature search and compared the premature termination codon context sequences with reported positive and negative read-through induction, identifying a potential role for nucleotide positions −9, −8, −3, −2, +13 and +14 (the first nucleotide of the stop codon is assigned as +1). The Pygm p.R50X mutation presents TGA as a stop codon, G nucleotides at positions −1 and −9, and a C nucleotide at −3, which potentially generate a good context for read-through induction, counteracted by the presence of C at −2 and its absence at +4.

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“…This process is driven by a quartenary complex consisting of a specialised selenocysteine tRNAsec, a specific elongation factor, a specific RNA secondary structure named SECIS, and GTP. Interestingly, aminoglycosides have been proposed to promote also SECIS-mediated translation [166]. X-ray crystallography and single-molecule FRET analysis revealed that several aminoglycosides such as G418 and gentamicin can directly interact with the 80S eukaryotic ribosome at multiple sites in the large and small subunits.…”

Section: Aminoglycoside Compoundsmentioning

confidence: 99%

Nonsense Suppression Therapy: New Hypothesis for the Treatment of Inherited Bone Marrow Failure Syndromes

Bezzerri

Api

Allegri

et al. 2020

IJMS

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Inherited bone marrow failure syndromes (IBMFS) are a group of cancer-prone genetic diseases characterized by hypocellular bone marrow with impairment in one or more hematopoietic lineages. The pathogenesis of IBMFS involves mutations in several genes which encode for proteins involved in DNA repair, telomere biology and ribosome biogenesis. The classical IBMFS include Shwachman–Diamond syndrome (SDS), Diamond–Blackfan anemia (DBA), Fanconi anemia (FA), dyskeratosis congenita (DC), and severe congenital neutropenia (SCN). IBMFS are associated with high risk of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and solid tumors. Unfortunately, no specific pharmacological therapies have been highly effective for IBMFS. Hematopoietic stem cell transplantation provides a cure for aplastic or myeloid neoplastic complications. However, it does not affect the risk of solid tumors. Since approximately 28% of FA, 24% of SCN, 21% of DBA, 20% of SDS, and 17% of DC patients harbor nonsense mutations in the respective IBMFS-related genes, we discuss the use of the nonsense suppression therapy in these diseases. We recently described the beneficial effect of ataluren, a nonsense suppressor drug, in SDS bone marrow hematopoietic cells ex vivo. A similar approach could be therefore designed for treating other IBMFS. In this review we explain in detail the new generation of nonsense suppressor molecules and their mechanistic roles. Furthermore, we will discuss strengths and limitations of these molecules which are emerging from preclinical and clinical studies. Finally we discuss the state-of-the-art of preclinical and clinical therapeutic studies carried out for IBMFS.

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Aminoglycoside-mediated promotion of translation readthrough occurs through a non-stochastic mechanism that competes with translation termination

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Cited by 22 publications

References 43 publications

Suppression of Nonsense Mutations by New Emerging Technologies

Suppression of Nonsense Mutations by New Emerging Technologies

Absence of p.R50X Pygm read-through in McArdle disease cellular models

Nonsense Suppression Therapy: New Hypothesis for the Treatment of Inherited Bone Marrow Failure Syndromes

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