Novel insights into the roles of tRNA-derived small RNAs

Pan, Qiyu; Han, Tae-Ho; Li, Guoping

doi:10.1080/15476286.2021.1922009

Cited by 24 publications

(25 citation statements)

References 97 publications

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“…Second, our data raise questions about the biochemical nature of the RNAs delivered to the zygote upon fertilization. Regulatory functions have been identified for multiple solitary 5' or 3' tRNA fragments in isolation [8,10,[42][43][44][45], suggesting numerous potential regulatory roles for sperm-delivered tRFs in the early embryo. However, given our finding that for many tRNAs both 5' and 3' tRNA halves can be found in sperm at similar abundance, it will be important to understand the biochemical context in which these RNAs are delivered to the zygote.…”

Section: Revisiting the Mouse Sperm Rna Payloadmentioning

confidence: 99%

Deep sequencing of yeast and mouse tRNAs and tRNA fragments using OTTR

Gustafsson

Galan

et al. 2022

Preprint

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Among the major classes of RNAs in the cell, tRNAs remain the most difficult to characterize via deep sequencing approaches, as tRNA secondary structure and nucleotide modifications can both interfere with cDNA synthesis by commonly-used reverse transcriptases (RTs). Here, we benchmark a recently-developed RNA cloning protocol, termed Ordered Two-Template Relay (OTTR), to characterize intact tRNAs and tRNA fragments in budding yeast and in mouse tissues. We find that OTTR robustly captures full-length tRNAs in budding yeast and in mouse testis, with relatively low levels of premature termination at known barriers - 1-methylguanine, N2,N2-dimethylguanine, and 1-methyladenine - to typical reverse transcriptases. Moreover, these and several other nucleotide modifications leave misincorporation signatures in OTTR datasets which enables their detection without any additional protocol steps. Turning to analysis of small RNAs such as tRNA cleavage products, we compare OTTR with several standard small RNA-Seq protocols, finding that OTTR provides the most accurate picture of tRNA fragment levels by comparison to "ground truth" Northern blots. Applying this protocol to mature mouse spermatozoa, our data dramatically alter our understanding of the small RNA cargo of mature mammalian sperm, revealing a far more complex population of tRFs - including both 5' and 3' tRNA halves derived from the majority of tRNAs - than previously appreciated. Taken together, our data confirm the superior performance of OTTR to commercial protocols in analysis of tRNA fragments, and force a reappraisal of potential epigenetic functions of the sperm small RNA payload.

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Section: Revisiting the Mouse Sperm Rna Payloadmentioning

confidence: 99%

Deep sequencing of yeast and mouse tRNAs and tRNA fragments using OTTR

Gustafsson

Galan

et al. 2022

Preprint

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“…It is increasingly apparent that tRFs exhibit crucial roles in numerous biological processes, such as mRNA stabilization, miRNA-like post-transcriptional silencing and regulation of protein translation [ 18 ]. Interestingly, an ever-growing number of studies have documented the deregulation of tRFs in numerous human malignancies, along with their active involvement in cancer onset and progression [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

tRNAGlyGCC-Derived Internal Fragment (i-tRF-GlyGCC) in Ovarian Cancer Treatment Outcome and Progression

Panoutsopoulou

Dreyer

Dorn

et al. 2021

Cancers

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Epithelial ovarian cancer (EOC) remains a highly-lethal gynecological malignancy, characterized by frequent recurrence, chemotherapy resistance and poor 5-year survival. Identifying novel predictive molecular markers remains an overdue challenge in the disease’s clinical management. Herein, in silico analysis of TCGA-OV highlighted the tRNA-derived internal fragment (i-tRF-GlyGCC) among the most abundant tRFs in ovarian tumors, while target prediction and gene ontology (GO) enrichment analysis predicted its implication in key biological processes. Thereafter, i-tRF-GlyGCC levels were quantified in a screening EOC (n = 98) and an institutionally-independent serous ovarian cancer (SOC) validation cohort (n = 100, OVCAD multicenter study). Disease progression and patient death were used as clinical endpoints for the survival analysis. Internal validation was performed by bootstrap analysis and the clinical net benefit was estimated by decision curve analysis. The analysis highlighted the significant association of i-tRF-GlyGCC with advanced FIGO stages, suboptimal debulking and most importantly, with early progression and poor overall survival of EOC patients. The OVCAD validation cohort corroborated the unfavorable predictive value of i-tRF-GlyGCC in EOC. Ultimately, evaluation of i-tRF-GlyGCC with the established/clinically used prognostic markers offered superior patient risk-stratification and enhanced clinical benefit in EOC prognosis. In conclusion, i-tRF-GlyGCC assessment could aid towards personalized prognosis and support precision medicine decisions in EOC.

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“…It is also possible that tRNA modifications act through other processes such as RNA sequestration, or the generation of tRNA-derived fragments (tRFs/tiRFs) [90] obtained by the endonuclease cleavage of tRNAs (mainly in the D-Loop, TΨC-Loop and anticodon-Loop), either in normal or stressed conditions. Such tRFs/tiRFs are involved in various physiological and pathological processes by modulating RNA stability or translation [62].…”

Section: ψ35/38/39mentioning

confidence: 99%

The Importance of the Epi-Transcriptome in Translation Fidelity

Valadon

Namy

2021

ncRNA

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RNA modifications play an essential role in determining RNA fate. Recent studies have revealed the effects of such modifications on all steps of RNA metabolism. These modifications range from the addition of simple groups, such as methyl groups, to the addition of highly complex structures, such as sugars. Their consequences for translation fidelity are not always well documented. Unlike the well-known m6A modification, they are thought to have direct effects on either the folding of the molecule or the ability of tRNAs to bind their codons. Here we describe how modifications found in tRNAs anticodon-loop, rRNA, and mRNA can affect translation fidelity, and how approaches based on direct manipulations of the level of RNA modification could potentially be used to modulate translation for the treatment of human genetic diseases.

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Novel insights into the roles of tRNA-derived small RNAs

Cited by 24 publications

References 97 publications

Deep sequencing of yeast and mouse tRNAs and tRNA fragments using OTTR

Deep sequencing of yeast and mouse tRNAs and tRNA fragments using OTTR

tRNAGlyGCC-Derived Internal Fragment (i-tRF-GlyGCC) in Ovarian Cancer Treatment Outcome and Progression

The Importance of the Epi-Transcriptome in Translation Fidelity

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