Authors: Xiaoqiang Zhu, Victor Emmanuel Cruz, He Zhang...

The CCR4-NOT complex is a major regulator of eukaryotic messenger RNA (mRNA) stability. Slow decoding during translation promotes association of CCR4-NOT with ribosomes, accelerating mRNA degradation. We applied selective ribosome profiling to further investigate the determinants of CCR4-NOT recruitment to ribosomes in mammalian cells. This revealed that specific arginine codons in the P-site are strong signals for ribosomal recruitment of human CNOT3, a CCR4-NOT subunit. Cryo-electron microscopy and transfer RNA (tRNA) mutagenesis demonstrated that the D-arms of select arginine tRNAs interact with CNOT3 and promote its recruitment whereas other tRNA D-arms sterically clash with CNOT3. These effects link codon content to mRNA stability. Thus, in addition to their canonical decoding function, tRNAs directly engage regulatory complexes during translation, a mechanism we term P-site tRNA-mediated mRNA decay.

Topics: Humans; Arginine; Codon; Cryoelectron Microscopy; HEK293 Cells; Protein Biosynthesis; Ribosomes; RNA Stability; RNA, Messenger; RNA, Transfer; RNA, Transfer, Arg; Transcription Factors; Jurkat Cells

PubMed: 39571015
DOI: 10.1126/science.adq8587

Review

Authors: Liou Zhang, Jie Liu, Yang Hou...

tRNA-derived small RNAs (tsRNAs) are non-coding small RNAs produced by specific endonucleases following the processing and splicing of precursor or mature tRNAs upon starvation, oxidative stress, hypoxia, and other adverse conditions. tRNAs are classified into two major categories, tRNA fragments (tRFs) and tRNA-derived stress-induced small RNAs (tiRNAs), based on differences in splice sites. With the development of high-throughput sequencing technologies in recent years, tsRNAs have been found to have important biological functions, including inhibition of apoptosis, epigenetic regulation, cell-cell communication, translation, and regulation of gene expression. Additionally, these molecules have been found to be aberrantly expressed in various diseases and to be involved in several pathological processes. In this article, the classification and nomenclature, biological functions, and potential use of tsRNAs as diagnostic biomarkers and therapeutic targets in non-neoplastic diseases are reviewed. Although tsRNA research is at its infancy, their potential in the treatment of non-tumor diseases warrants further investigation.

Topics: Epigenesis, Genetic; RNA, Transfer

PubMed: 37973899
DOI: 10.1038/s41419-023-06250-9

Review

Authors: Tao Pan

Transfer RNA (tRNA) is present at tens of millions of transcripts in a human cell and is the most abundant RNA in moles among all cellular RNAs. tRNA is also the most extensively modified RNA with, on an average, 13 modifications per molecule. The primary function of tRNA as the adaptor of amino acids and the genetic code in protein synthesis is well known. tRNA modifications play multi-faceted roles in decoding and other cellular processes. The abundance, modification, and aminoacylation (charging) levels of tRNAs contribute to mRNA decoding in ways that reflect the cell type and its environment; however, how these factors work together to maximize translation efficiency remains to be understood. tRNAs also interact with many proteins not involved in translation and this may coordinate translation activity and other processes in the cell. This review focuses on the modifications and the functional genomics of human tRNA and discusses future perspectives on the explorations of human tRNA biology.

Topics: Acylation; Amination; Animals; Base Sequence; Genomics; Humans; Methylation; RNA Processing, Post-Transcriptional; RNA, Transfer

PubMed: 29463900
DOI: 10.1038/s41422-018-0013-y

Review

Authors: Samoil Sekulovski, Simon Trowitzsch

Transfer RNAs (tRNAs) are highly structured non-coding RNAs which play key roles in translation and cellular homeostasis. tRNAs are initially transcribed as precursor molecules and mature by tightly controlled, multistep processes that involve the removal of flanking and intervening sequences, over 100 base modifications, addition of non-templated nucleotides and aminoacylation. These molecular events are intertwined with the nucleocytoplasmic shuttling of tRNAs to make them available at translating ribosomes. Defects in tRNA processing are linked to the development of neurodegenerative disorders. Here, we summarize structural aspects of tRNA processing steps with a special emphasis on intron-containing tRNA splicing involving tRNA splicing endonuclease and ligase. Their role in neurological pathologies will be discussed. Identification of novel RNA substrates of the tRNA splicing machinery has uncovered functions unrelated to tRNA processing. Future structural and biochemical studies will unravel their mechanistic underpinnings and deepen our understanding of neurological diseases.

Topics: Introns; Nucleic Acid Conformation; RNA Processing, Post-Transcriptional; RNA Splicing; RNA, Transfer

PubMed: 35728022
DOI: 10.1515/hsz-2021-0406

Authors: Yaoyao Xie, Shuangshuang Zhang, Xiuchong Yu...

Gastric cancer (GC) is a particularly malignant disease; thus, early diagnosis and treatment are especially important. Transfer RNA-derived small RNAs (tsRNAs) have been implicated in the onset and progression of various cancers. Therefore, the aim of this study was to explore the role of tRF-18-79MP9P04 (previously named tRF-5026a) in the onset and progression of GC. Expression levels of tRF-18-79MP9P04 were quantified in gastric mucosa specimens of healthy controls and plasma samples of patients with different stages of GC. The results showed that plasma levels of tRF-18-79MP9P04 were significantly decreased in the early and advanced stages of GC. The results of the nucleocytoplasmic separation assay found that tRF-18-79MP9P04 was localized in the nuclei of GC cells. High-throughput transcriptome sequencing identified genes regulated by tRF-18-79MP9P04 in GC cells, and the function of tRF-18-79MP9P04 was predicted by bioinformatics. Collectively, the findings of this study suggest that tRF-18-79MP9P04 would be useful as non-invasive biomarker for early diagnosis of GC and is related to cornification, the type I interferon signaling pathway, RNA polymerase II activities, and DNA binding.

Topics: Humans; Stomach Neoplasms; RNA, Transfer; Biomarkers

PubMed: 37387464
DOI: 10.1177/15353702231179415

Review

Authors: Yasutoshi Akiyama, Pavel Ivanov

Oxidative stress refers to excessive intracellular levels of reactive oxygen species (ROS) due to an imbalance between ROS production and the antioxidant defense system. Under oxidative stress conditions, cells trigger various stress response pathways to protect themselves, among which repression of messenger RNA (mRNA) translation is one of the key hallmarks promoting cell survival. This regulation process minimizes cellular energy consumption, enabling cells to survive in adverse conditions and to promote recovery from stress-induced damage. Recent studies suggest that transfer RNAs (tRNAs) play important roles in regulating translation as a part of stress response under adverse conditions. In particular, research relying on high-throughput techniques such as next-generation sequencing and mass spectrometry approaches has given us detailed information on mechanisms such as individual tRNA dynamics and crosstalk among post-transcriptional modifications. Oxidative stress leads to dynamic tRNA changes, including their localization, cleavage, and alteration of expression profiles and modification patterns. Growing evidence suggests that these changes not only are tightly regulated by stress response mechanisms, but also can directly fine-tune the translation efficiency, which contributes to cell- or tissue-specific response to oxidative stress. In this review, we describe recent advances in the understanding of the dynamic changes of tRNAs caused by oxidative stress. We also highlight the emerging roles of tRNAs in translation regulation under the condition of oxidative stress. In addition, we discuss future perspectives in this research field. . 40, 715-735.

Topics: Reactive Oxygen Species; Oxidative Stress; Proteins; Protein Biosynthesis; RNA, Transfer

PubMed: 37767630
DOI: 10.1089/ars.2022.0206

Review

Authors: Sarah K Schultz, Ute Kothe

Transfer RNAs (tRNAs) are the most highly modified cellular RNAs, both with respect to the proportion of nucleotides that are modified within the tRNA sequence and with respect to the extraordinary diversity in tRNA modification chemistry. However, the functions of many different tRNA modifications are only beginning to emerge. tRNAs have two general clusters of modifications. The first cluster is within the anticodon stem-loop including several modifications essential for protein translation. The second cluster of modifications is within the tRNA elbow, and roles for these modifications are less clear. In general, tRNA elbow modifications are typically not essential for cell growth, but nonetheless several tRNA elbow modifications have been highly conserved throughout all domains of life. In addition to forming modifications, many tRNA modifying enzymes have been demonstrated or hypothesized to also play an important role in folding tRNA acting as tRNA chaperones. In this review, we summarize the known functions of tRNA modifying enzymes throughout the lifecycle of a tRNA molecule, from transcription to degradation. Thereby, we describe how tRNA modification and folding by tRNA modifying enzymes enhance tRNA maturation, tRNA aminoacylation, and tRNA function during protein synthesis, ultimately impacting cellular phenotypes and disease.

Topics: RNA, Transfer; Humans; RNA Processing, Post-Transcriptional; Protein Biosynthesis; Animals; Anticodon

PubMed: 38908752
DOI: 10.1016/j.jbc.2024.107488

Authors: Ralph Panstruga, Pietro Spanu

According to current textbooks, the principal task of transfer and ribosomal RNAs (tRNAs and rRNAs, respectively) is synthesizing proteins. During the last decade, additional cellular roles for precisely processed tRNA and rRNAs fragments have become evident in all kingdoms of life. These RNA fragments were originally overlooked in transcriptome datasets or regarded as unspecific degradation products. Upon closer inspection, they were found to engage in a variety of cellular processes, in particular the modulation of translation and the regulation of gene expression by sequence complementarity- and Argonaute protein-dependent gene silencing. More recently, the presence of tRNA and rRNA fragments has also been recognized in the context of plant-microbe interactions, both on the plant and the microbial side. While most of these fragments are likely to affect endogenous processes, there is increasing evidence for their transfer across kingdoms in the course of such interactions; these processes may involve mutual exchange in association with extracellular vesicles. Here, we summarize the state-of-the-art understanding of tRNA and rRNA fragment's roles in the context of plant-microbe interactions, their potential biogenesis, presumed delivery routes, and presumptive modes of action.

Topics: RNA, Ribosomal; RNA, Transfer; RNA

PubMed: 37985402
DOI: 10.1111/nph.19409

Authors: Christopher Francklyn

Topics: Amino Acyl-tRNA Synthetases; Animals; Humans; RNA, Transfer

PubMed: 28109447
DOI: 10.1016/j.ymeth.2016.12.009

Review

Authors: Sipeng Wu, Xiang Li, Geng Wang...

tRNA-like structures (TLSs) were first identified in the RNA genomes of turnip yellow mosaic virus. Since then, TLSs have been found in many other species including mammals, and the RNAs harboring these structures range from viral genomic RNAs to mRNAs and noncoding RNAs. Some progress has also been made on understanding their functions that include regulation of RNA replication, translation enhancement, RNA-protein interaction, and more. In this review, we summarize the current knowledge about the regulations and functions of these TLSs. Possible future directions of the field are also briefly discussed.

Topics: Genome, Viral; Nucleic Acid Conformation; RNA, Transfer; RNA, Viral; Tymovirus

PubMed: 34117728
DOI: 10.1111/febs.16070