Impact of tRNA Modifications and tRNA-Modifying Enzymes on Proteostasis and Human Disease

Pereira, Marisa; Francisco, Stephany; Varanda, Ana Sofia; Santos, Mafalda; Santos, Manuel A. S.; Soares, Ana Raquel

doi:10.3390/ijms19123738

Cited by 103 publications

(88 citation statements)

References 105 publications

(169 reference statements)

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“…tRNAs are by far the most post-transcriptionally modified gene class (Boccaletto et al 2018). Research is just now starting to tease apart the many roles these modifications play Phizicky and Alfonzo 2010;Pereira et al 2018;de Crecy-Lagard et al 2019). Not all modifications are detectable through sequencing, but it has been estimated that RT-based methods can identify approximately 25% of tRNA modifications in humans (Clark et al 2016), and the modifications that can be detected by sequencing are known to have critical roles in tRNA folding, rigidity and stability (Pan 2018).…”

Section: The Landscape Of Base Modifications In Plant Trnasmentioning

confidence: 99%

Combining tRNA sequencing methods to characterize plant tRNA expression and post-transcriptional modification

Warren

Salinas‐Giegé

Hummel

et al. 2019

Preprint

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Differences in tRNA expression have been implicated in a remarkable number of biological processes.There is growing evidence that tRNA genes can play dramatically different roles depending on both expression and post-transcriptional modification, yet sequencing tRNAs to measure abundance and detect modifications remains challenging. Their secondary structure and extensive post-transcriptional modifications interfere with RNA-seq library preparation methods and have limited the utility of highthroughput sequencing technologies. Here, we combine two modifications to standard RNA-seq methods by treating with the demethylating enzyme AlkB and ligating with tRNA-specific adapters in order to sequence tRNAs from four species of flowering plants, a group that has been shown to have some of the most extensive rates of post-transcriptional tRNA modifications. This protocol has the advantage of detecting full-length tRNAs and sequence variants that can be used to infer many post-transcriptional modifications. We used the resulting data to produce a modification index of almost all unique reference tRNAs in Arabidopsis thaliana, which exhibited many anciently conserved similarities with humans but also positions that appear to be "hot spots" for modifications in angiosperm tRNAs. We also found evidence based on northern blot analysis and droplet digital PCR that, even after demethylation treatment, tRNA-seq can produce highly biased estimates of absolute expression levels most likely due to biased reverse transcription. Nevertheless, the generation of full-length tRNA sequences with modification data is still promising for assessing differences in relative tRNA expression across treatments, tissues or subcellular fractions and help elucidate the functional roles of tRNA modifications.

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Section: The Landscape Of Base Modifications In Plant Trnasmentioning

confidence: 99%

Combining tRNA sequencing methods to characterize plant tRNA expression and post-transcriptional modification

Warren

Salinas‐Giegé

Hummel

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…While there are several conserved locations for tRNA modifications within 70–90 nucleotides long tRNAs, specific modification at the anticodon loop is vital to reprogram translation under stress . According to their importance, perturbations in tRNA modifications are broadly associated with multiple human pathologies (discussed in Zhang and co‐workers).…”

Section: Reprogramming Of Protein Synthesis Under Stressmentioning

confidence: 99%

Translational Control under Stress: Reshaping the Translatome

2019

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Adequate reprogramming of cellular metabolism in response to stresses or suboptimal growth conditions involves a myriad of coordinated changes that serve to promote cell survival. As protein synthesis is an energetically expensive process, its regulation under stress is of critical importance. Reprogramming of messenger RNA (mRNA) translation involves well‐understood stress‐activated kinases that target components of translation initiation machinery, resulting in the robust inhibition of general translation and promotion of the translation of stress‐responsive proteins. Translational arrest of mRNAs also results in the accumulation of transcripts in cytoplasmic foci called stress granules. Recent studies focus on the key roles of transfer RNA (tRNA) in stress‐induced translational reprogramming. These include stress‐specific regulation of tRNA pools, codon‐biased translation influenced by tRNA modifications, tRNA miscoding, and tRNA cleavage. In combination, signal transduction pathways and tRNA metabolism changes regulate translation during stress, resulting in adaptation and cell survival. This review examines molecular mechanisms that regulate protein synthesis in response to stress.

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“…13 Specially, suppressor tRNAs are molecules that bear mutations in the anticodon allowing a stop codon to be recognized as a regular codon, resulting in amino acid incorporation instead. 16 During this process, the 5' leader and 3' trailer in the pre-tRNA are removed by ribonuclease P (RNase P) and RNase Z respectively. 16 During this process, the 5' leader and 3' trailer in the pre-tRNA are removed by ribonuclease P (RNase P) and RNase Z respectively.…”

Section: Structure Of Trnasmentioning

confidence: 99%

“…14,15 In fact, approximately 610 tRNA genes in humans are transcribed into primary products, precursor tRNAs (pre-tRNAs), under the catalysis of RNA polymerase III (Pol III), which must then undergo a series of complex processing to transform into mature tRNAs. 16 During this process, the 5' leader and 3' trailer in the pre-tRNA are removed by ribonuclease P (RNase P) and RNase Z respectively. [17][18][19] Subsequently, a CCA sequence associated with aminoacylation will be added to the 3' end by tRNA nucleotidyltransferase 1 (TRNT1).…”

Section: Structure Of Trnasmentioning

confidence: 99%

The tRNA‐associated dysregulation in immune responses and immune diseases

et al. 2019

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Transfer RNA (tRNA), often considered as a housekeeping molecule, mainly participates in protein translation by transporting amino acids to the ribosome. Nevertheless, accumulating evidence has shown that tRNAs are closely related to various physiological and pathological processes. The proper functioning of the immune system is the key to human health. The aim of this review is to investigate the relationships between tRNAs and the immune system. We detail the biogenesis and structure of tRNAs and summarize the pathogen tRNA-mediated infection and host responses. In addition, we address recent advances in different aspects of tRNA-associated dysregulation in immune responses and immune diseases, such as tRNA molecules, tRNA modifications, tRNA derivatives and tRNA aminoacylation. Therefore, tRNAs play an important role in immune regulation. Although our knowledge of tRNAs in the context of immunity remains, for the most part, unknown, this field deserves in-depth research to provide new ideas for the treatment of immune diseases. K E Y W O R D Sbiogenesis, immune diseases, immune responses, tRNA F I G U R E 1 The biogenesis and structure of tRNAs. tRNA: Transfer RNA; Pol III: RNA polymerase III; pre-tRNA: Precursor tRNA; mRNA: Messenger RNA; aaRS: Aminoacyl-tRNA synthetase; tsRNA: tRNA-derived small RNA; tRF: tRNA-derived fragment; tiRNA: tRNA-derived stress-induced RNA

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Impact of tRNA Modifications and tRNA-Modifying Enzymes on Proteostasis and Human Disease

Cited by 103 publications

References 105 publications

Combining tRNA sequencing methods to characterize plant tRNA expression and post-transcriptional modification

Combining tRNA sequencing methods to characterize plant tRNA expression and post-transcriptional modification

Translational Control under Stress: Reshaping the Translatome

The tRNA‐associated dysregulation in immune responses and immune diseases

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