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Near-cognate tRNAs increase the efficiency and precision of pseudouridine-mediated readthrough of premature termination codons

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE237633 | GEO | 2024/01/29

REPOSITORIES: GEO

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Near-cognate tRNAs increase the efficiency and precision of pseudouridine-mediated readthrough of premature termination codons [PRAISE]

Project description:Nonsense mutations, responsible for ~11% of genetic diseases, create premature stop codons (PTCs) and lead to truncated and often non-functional proteins. Recently, programmable RNA pseudouridylation has emerged as a new type of RNA base editor to suppress PTCs. However, current methods suffer from low efficiency and limited precision. Here, we develop RESTART v3, an updated version of RESTART, which utilizes near-cognate tRNAs to improve the readthrough efficiency of pseudouridine-modified PTCs. We show an average of ~5-fold higher editing efficiency than RESTART v2 in cultured cells, currently the most active RNA pseudouridylation tool to mediate PTC readthrough. Moreover, RESTART v3 achieves functional PTC readthrough in disease cell models of cystic fibrosis and Hurler syndrome. Furthermore, RESTART v3 enables accurate incorporation of the original amino acid for nearly half of the PTC sites, considering the naturally occurring frequencies of sense to nonsense codons. In line with the benign off-target effect of RESTART, RESTART v3 does not change the coding information nor the expression level of transcripts with off-target editing; except for the specifically overexpressed tRNA molecule, it does not alter the expression level of endogenous tRNA pool. Overall, RESTART v3 represents an enhanced RNA base editor with increased efficiency and accuracy.

2024-01-29 | GSE237632 | GEO

Near-cognate tRNAs increase the efficiency and precision of pseudouridine-mediated readthrough of premature termination codons [RNA-seq]

2024-01-29 | GSE237631 | GEO

Near-cognate tRNAs increase the efficiency and precision of pseudouridine-mediated readthrough of premature termination codons [tRNA-seq]

2024-01-29 | GSE237630 | GEO

Near-cognate tRNAs increase the efficiency and precision of pseudouridine-mediated readthrough of premature termination codons [Target-seq]

2024-01-29 | GSE237629 | GEO

Near-cognate tRNAs increase the efficiency and precision of pseudouridine-mediated readthrough of premature termination codons

Project description:Near-cognate tRNAs increase the efficiency and precision of pseudouridine-mediated readthrough of premature termination codons

| PRJNA996057 | ENA

Near-cognate tRNAs increase the efficiency and precision of pseudouridine-mediated readthrough of premature termination codons [PRAISE]

Project description:Near-cognate tRNAs increase the efficiency and precision of pseudouridine-mediated readthrough of premature termination codons [PRAISE]

| PRJNA996070 | ENA

Near-cognate tRNAs increase the efficiency and precision of pseudouridine-mediated readthrough of premature termination codons [tRNA-seq]

Project description:Near-cognate tRNAs increase the efficiency and precision of pseudouridine-mediated readthrough of premature termination codons [tRNA-seq]

| PRJNA996068 | ENA

Near-cognate tRNAs increase the efficiency and precision of pseudouridine-mediated readthrough of premature termination codons [RNA-seq]

Project description:Near-cognate tRNAs increase the efficiency and precision of pseudouridine-mediated readthrough of premature termination codons [RNA-seq]

| PRJNA996069 | ENA

Near-cognate tRNAs increase the efficiency and precision of pseudouridine-mediated readthrough of premature termination codons [Target-seq]

Project description:Near-cognate tRNAs increase the efficiency and precision of pseudouridine-mediated readthrough of premature termination codons [Target-seq]

| PRJNA996067 | ENA

Rules of UGA-N decoding by near-cognate tRNAs and analysis of readthrough on short uORFs in yeast.

Project description:The molecular mechanism of stop codon recognition by the release factor eRF1 in complex with eRF3 has been described in great detail; however, our understanding of what determines the difference in termination efficiencies among various stop codon tetranucleotides and how near-cognate (nc) tRNAs recode stop codons during programmed readthrough in Saccharomyces cerevisiae is still poor. Here, we show that UGA-C as the only tetranucleotide of all four possible combinations dramatically exacerbated the readthrough phenotype of the stop codon recognition-deficient mutants in eRF1. Since the same is true also for UAA-C and UAG-C, we propose that the exceptionally high readthrough levels that all three stop codons display when followed by cytosine are partially caused by the compromised sampling ability of eRF1, which specifically senses cytosine at the +4 position. The difference in termination efficiencies among the remaining three UGA-N tetranucleotides is then given by their varying preferences for nc-tRNAs. In particular, UGA-A allows increased incorporation of Trp-tRNA whereas UGA-G and UGA-C favor Cys-tRNA. Our findings thus expand the repertoire of general decoding rules by showing that the +4 base determines the preferred selection of nc-tRNAs and, in the case of cytosine, it also genetically interacts with eRF1. Finally, using an example of the GCN4 translational control governed by four short uORFs, we also show how the evolution of this mechanism dealt with undesirable readthrough on those uORFs that serve as the key translation reinitiation promoting features of the GCN4 regulation, as both of these otherwise counteracting activities, readthrough versus reinitiation, are mediated by eIF3.

| S-EPMC4748822 | biostudies-literature

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