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

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

PROVIDER: PRJNA996068 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25321744_1.fastq.gz	Fastqsanger.gz
	SRR25321744_2.fastq.gz	Fastqsanger.gz
	SRR25321745_1.fastq.gz	Fastqsanger.gz
	SRR25321745_2.fastq.gz	Fastqsanger.gz
	SRR25321746_1.fastq.gz	Fastqsanger.gz

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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]

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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 [Target-seq]

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

| PRJNA996067 | 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

Efficient Suppression of Premature Termination Codons by Engineered Pyrrolysine tRNAs

Project description:Mutations that introduce premature termination codons (PTCs) within protein-coding genes are associated with incurable and severe genetic diseases. Many PTC-associated disorders are life-threatening and have no approved medical treatment options. Suppressor transfer RNAs (sup-tRNAs) with the capacity to promote translational readthrough of PTCs represent a promising therapeutic strategy to treat these conditions; however, developing novel sup-tRNAs with high efficiency and specificity often requires extensive engineering and screening. Moreover, these efforts are not always successful at producing more efficient sup-tRNAs. Here we show that the pyrrolysine tRNA (tRNAPyl), which naturally translates the UAG stop codon, offers an attractive scaffold for developing potent sup-tRNAs that restore protein synthesis from PTC-containing genes. We created a series of rationally designed Pyrrolysine tRNA Scaffold Suppressor-tRNAs (PASS-tRNAs) that are substrates of bacterial and human alanyl-tRNA synthetase. Using a PTC-containing reporter gene, PASS-tRNAs restore protein synthesis to wild-type levels in bacterial cells. In human cells, PASS-tRNAs display robust and consistent translation activity in two distinct PTC reporter genes with high codon specificity and no observed cytotoxic effects. Collectively, these results unveil a new class of highly efficient sup-tRNAs with great potential for tRNA-based therapeutics.

2025-02-20 | PXD044322 | Pride

Deciphering the reading of the genetic code by near-cognate tRNA

Project description:Some codons of the genetic code can be read not only by cognate, but also by near-cognate tRNAs. This flexibility is thought to be conferred mainly by a mismatch between the third base of the codon and the first of the anticodon (the so-called wobble position). However, this simplistic explanation underestimates the importance of nucleotide modifications in the decoding process. Using a system in which only near-cognate tRNAs can decode a specific codon, we investigated the role of six modifications of the anticodon, or adjacent nucleotides, of the tRNAs specific for Tyr, Gln, Lys, Trp, Cys and Arg in Saccharomyces cerevisiae. Modifications almost systematically rendered these tRNAs able to act as near-cognate tRNAs at stop codons, even though they involve non-canonical base-pairs, without markedly affecting their ability to decode cognate or near-cognate sense codons. These findings reveal an important effect of modifications to tRNA decoding with implications for understanding the flexibility of the genetic code.

2018-04-04 | GSE108772 | GEO

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