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      tRNA-derived fragments: Mechanisms underlying their regulation of gene expression and potential applications as therapeutic targets in cancers and virus infections

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          Abstract

          tRNA-derived fragments (tRFs) are a new category of regulatory noncoding RNAs with distinct biological functions in cancers and stress-induced diseases. Herein, we first summarize the classification and biogenesis of tRFs. tRFs are produced from pre-tRNAs or mature tRNAs. Based on the incision loci, tRFs are classified into several types: tRF-1, tRF-2, tRF-3, tRF-5, and i-tRF. Some tRFs participate in posttranscriptional regulation through microRNA-like actions or by displacing RNA binding proteins and regulating protein translation by promoting ribosome biogenesis or interfering with translation initiation. Other tRFs prevent cell apoptosis by binding to cytochrome c or promoting virus replication. More importantly, the dysregulation of tRFs has important clinical implications. They are potential diagnostic and prognostic biomarkers of gastric cancer, liver cancer, breast cancer, prostate cancer, and chronic lymphocytic leukemia. tRFs may become new therapeutic targets for the treatment of diseases such as hepatocellular carcinoma and respiratory syncytial virus infection. Finally, we point out the existing problems and future research directions associated with tRFs. In conclusion, the current progress in the research of tRFs reveals that they have important clinical implications and may constitute novel molecular therapeutic targets for modulating pathological processes.

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          Most cited references72

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          Insights into RNA biology from an atlas of mammalian mRNA-binding proteins.

          RNA-binding proteins (RBPs) determine RNA fate from synthesis to decay. Employing two complementary protocols for covalent UV crosslinking of RBPs to RNA, we describe a systematic, unbiased, and comprehensive approach, termed "interactome capture," to define the mRNA interactome of proliferating human HeLa cells. We identify 860 proteins that qualify as RBPs by biochemical and statistical criteria, adding more than 300 RBPs to those previously known and shedding light on RBPs in disease, RNA-binding enzymes of intermediary metabolism, RNA-binding kinases, and RNA-binding architectures. Unexpectedly, we find that many proteins of the HeLa mRNA interactome are highly intrinsically disordered and enriched in short repetitive amino acid motifs. Interactome capture is broadly applicable to study mRNA interactome composition and dynamics in varied biological settings. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Endogenous tRNA-Derived Fragments Suppress Breast Cancer Progression via YBX1 Displacement.

            Upon exposure to stress, tRNAs are enzymatically cleaved, yielding distinct classes of tRNA-derived fragments (tRFs), yielding distinct classes of tRFs. We identify a novel class of tRFs derived from tRNA(Glu), tRNA(Asp), tRNA(Gly), and tRNA(Tyr) that, upon induction, suppress the stability of multiple oncogenic transcripts in breast cancer cells by displacing their 3' untranslated regions (UTRs) from the RNA-binding protein YBX1. This mode of post-transcriptional silencing is sequence specific, as these fragments all share a common motif that matches the YBX1 recognition sequence. Loss-of-function and gain-of-function studies, using anti-sense locked-nucleic acids (LNAs) and synthetic RNA mimetics, respectively, revealed that these fragments suppress growth under serum-starvation, cancer cell invasion, and metastasis by breast cancer cells. Highly metastatic cells evade this tumor-suppressive pathway by attenuating the induction of these tRFs. Our findings reveal a tumor-suppressive role for specific tRNA-derived fragments and describe a molecular mechanism for their action. This transcript displacement-based mechanism may generalize to other tRNA, ribosomal-RNA, and sno-RNA fragments.
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              A novel class of small RNAs: tRNA-derived RNA fragments (tRFs).

              New types of small RNAs distinct from microRNAs (miRNAs) are progressively being discovered in various organisms. In order to discover such novel small RNAs, a library of 17- to 26-base-long RNAs was created from prostate cancer cell lines and sequenced by ultra-high-throughput sequencing. A significant number of the sequences are derived from precise processing at the 5' or 3' end of mature or precursor tRNAs to form three series of tRFs (tRNA-derived RNA fragments): the tRF-5, tRF-3, and tRF-1 series. These sequences constitute a class of short RNAs that are second most abundant to miRNAs. Northern hybridization, quantitative RT-PCR, and splinted ligation assays independently measured the levels of at least 17 tRFs. To demonstrate the biological importance of tRFs, we further investigated tRF-1001, derived from the 3' end of a Ser-TGA tRNA precursor transcript that is not retained in the mature tRNA. tRF-1001 is expressed highly in a wide range of cancer cell lines but much less in tissues, and its expression in cell lines was tightly correlated with cell proliferation. siRNA-mediated knockdown of tRF-1001 impaired cell proliferation with the specific accumulation of cells in G2, phenotypes that were reversed specifically by cointroducing a synthetic 2'-O-methyl tRF-1001 oligoribonucleotide resistant to the siRNA. tRF-1001 is generated in the cytoplasm by tRNA 3'-endonuclease ELAC2, a prostate cancer susceptibility gene. Our data suggest that tRFs are not random by-products of tRNA degradation or biogenesis, but an abundant and novel class of short RNAs with precise sequence structure that have specific expression patterns and specific biological roles.
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                Author and article information

                Journal
                Theranostics
                Theranostics
                thno
                Theranostics
                Ivyspring International Publisher (Sydney )
                1838-7640
                2021
                1 January 2021
                : 11
                : 1
                : 461-469
                Affiliations
                [1 ]Department of Biochemistry and Molecular Biology and Zhejiang Key Laboratory of Pathophysiology, Medical School of Ningbo University, Ningbo 315211, China.
                [2 ]Department of Gastrointestinal Surgery, Ningbo First Hospital, Ningbo University, Ningbo 315010, China.
                Author notes
                ✉ Corresponding authors: E-mail: xiaobingxiu@ 123456nbu.edu.cn , or yanzhilong@ 123456nbu.edu.cn ; Tel: +86-574-87600758; Fax: +86-574-87608638.

                Competing Interests: The authors have declared that no competing interest exists.

                Article
                thnov11p0461
                10.7150/thno.51963
                7681095
                33391486
                229e1842-3fcc-4ebc-ab95-bbd8c3765ec2
                © The author(s)

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

                History
                : 14 August 2020
                : 2 October 2020
                Categories
                Review

                Molecular medicine
                trna-derived fragment (trf),mechanism,cancer,virus infection,therapeutic strategy

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