Coordination of transcription and processing of tRNA

Jarrous, Nayef; Mani, Dhivakar; Ramanathan, Aravind

doi:10.1111/febs.15904

Cited by 19 publications

(16 citation statements)

References 169 publications

(299 reference statements)

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“…Is the native-nonnative equilibrium dependent on spatiotemporal gene expression and cellular cofactors? Second, while our studies were performed with in vitro transcripts, it would be informative to examine how other cellular events, such as cotranscriptional RNA folding and modification (8,43,44), affect the conformational sampling of tRNAs.…”

Section: Discussionmentioning

confidence: 99%

Structural basis for impaired 5′ processing of a mutant tRNA associated with defects in neuronal homeostasis

Lai

Szymanski

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Significance Understanding and treating neurological disorders are global priorities. Some of these diseases are engendered by mutations that cause defects in the cellular synthesis of transfer RNAs (tRNAs), which function as adapter molecules that translate messenger RNAs into proteins. During tRNA biogenesis, ribonuclease P catalyzes removal of the transcribed sequence upstream of the mature tRNA. Here, we focus on a cytoplasmic tRNA Arg UCU that is expressed specifically in neurons and, when harboring a particular point mutation, contributes to neurodegeneration in mice. Our results suggest that this mutation favors stable alternative structures that are not cleaved by mouse ribonuclease P and motivate a paradigm that may help to understand the molecular basis for disease-associated mutations in other tRNAs.

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Section: Discussionmentioning

confidence: 99%

Structural basis for impaired 5′ processing of a mutant tRNA associated with defects in neuronal homeostasis

Lai

Szymanski

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…Removal of the intron is just one of many tRNA processing events and it remains unclear if tRNA splicing is coordinated with tRNA transcription, processing, and/or modification [reviewed in Jarrous et al (2021)]. Following transcription, by RNA Pol III nascent intron‐containing pre‐tRNAs are processed by three nucleases including the TSEN complex, RNase P, and RNase Z and there is growing evidence that suggests co‐transcriptional tRNA processing is occurring [reviewed in Jarrous et al (2021)]. tRNAs are the most heavily post‐transcriptional modified RNAs inside the cell and dysregulation of these modifications has been linked to neurological disease [reviewed in Das et al (2021) and Suzuki (2021)].…”

Section: Conclusion and Open Questions In Transfer Rna Splicingmentioning

confidence: 99%

Recent insights into the structure, function, and regulation of the eukaryotic transfer RNA splicing endonuclease complex

2022

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The splicing of transfer RNA (tRNA) introns is a critical step of tRNA maturation, for intron-containing tRNAs. In eukaryotes, tRNA splicing is a multi-step process that relies on several RNA processing enzymes to facilitate intron removal and exon ligation. Splicing is initiated by the tRNA splicing endonuclease (TSEN) complex which catalyzes the excision of the intron through its two nuclease subunits. Mutations in all four subunits of the TSEN complex are linked to a family of neurodegenerative and neurodevelopmental diseases known as pontocerebellar hypoplasia (PCH). Recent studies provide molecular insights into the structure, function, and regulation of the eukaryotic TSEN complex and are beginning to illuminate how mutations in the TSEN complex lead to neurodegenerative disease. Using new advancements in the prediction of protein structure, we created a three-dimensional model of the human TSEN complex. We review functions of the TSEN complex beyond tRNA splicing by highlighting recently identified substrates of the eukaryotic TSEN complex and discuss mechanisms for the regulation of tRNA splicing, by enzymes that modify cleaved tRNA exons and introns. Finally, we review recent biochemical and animal models that have worked to address the mechanisms that drive PCH and synthesize these studies with previous studies to try to better understand PCH pathogenesis.

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“…There are several groups of enzymes involved in tRF biogenesis. The 5′ leader sequence is a substrate for RNase P, producing the mature 5′ end of tRNA, while nuclease Z cleaves the 3′ trailer [ 19 , 20 ]. Moreover, it was suggested that the Dicer nuclease produces tRF-5 and tRF-3 fragments of a size similar to that of miRNA, i.e., 20–25-nucleotide long oligomers, which are cut by Dicer at the tRNA elbow end [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Characteristics of Transfer RNA-Derived Fragments Expressed during Human Renal Cell Development: The Role of Dicer in tRF Biogenesis

Kazimierczyk

Wojnicka

Biala

et al. 2022

IJMS

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tRNA-derived fragments participate in the regulation of many processes, such as gene silencing, splicing and translation in many organisms, ranging from bacteria to humans. We were interested to know how tRF abundance changes during the different stages of renal cell development. The research model used here consisted of the following human renal cells: hESCs, HEK-293T, HK-2 and A-489 kidney tumor cells, which, together, mimic the different stages of kidney development. The characteristics of the most abundant tRFs, tRFGly(CCC), tRFVal(AAC) and tRFArg(CCU), were presented. It was found that these parental tRNAs present in cells are the source of many tRFs, thus increasing the pool of potential regulatory RNAs. Indeed, a bioinformatic analysis showed the possibility that tRFGly(CCC) and tRRFVal(AAC) could regulate the activity of a range of kidney proteins. Moreover, the distribution of tRFs and the efficiency of their expression is similar in adult and embryonic stem cells. During the formation of tRFs, HK-2 cells resemble A-498 cancer cells more than other cells. Additionally, we postulate the involvement of Dicer nuclease in the formation of tRF-5b in all the analyzed tRNAs. To confirm this, 293T NoDice cells, which in the absence of Dicer activity do not generate tRF-5b, were used.

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Coordination of transcription and processing of tRNA

Cited by 19 publications

References 169 publications

Structural basis for impaired 5′ processing of a mutant tRNA associated with defects in neuronal homeostasis

Structural basis for impaired 5′ processing of a mutant tRNA associated with defects in neuronal homeostasis

Recent insights into the structure, function, and regulation of the eukaryotic transfer RNA splicing endonuclease complex

Characteristics of Transfer RNA-Derived Fragments Expressed during Human Renal Cell Development: The Role of Dicer in tRF Biogenesis

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