tRNA-Derived Fragments (tRFs): Emerging New Roles for an Ancient RNA in the Regulation of Gene Expression

This review will summarise the recent discoveries and current state of research on short noncoding RNAs derived from tRNAs—known as tRNA-derived fragments (tRFs). It will describe the features of the known subtypes of these RNAs; including sequence characteristics, protein interactors, expression characteristics, biogenesis, and similarity to canonical miRNA pathways. Also their role in regulating gene expression; including mediating translational suppression, will be discussed. We also highlight their potential use as biomarkers, functions in gene regulation and links to disease. Finally, this review will speculate as to the origin and rationale for the conservation of this novel class of noncoding RNAs amongst both prokaryotes and eukaryotes.

[1]  S. S. Ajay,et al.  Identification and functional characterization of tRNA-derived RNA fragments (tRFs) in respiratory syncytial virus infection. , 2013, Molecular therapy : the journal of the American Society of Gene Therapy.

[2]  R. Sachidanandam,et al.  A growth-essential Tetrahymena Piwi protein carries tRNA fragment cargo. , 2010, Genes & development.

[3]  Xiaoyong Bao,et al.  Respiratory Syncytial Virus Utilizes a tRNA Fragment to Suppress Antiviral Responses Through a Novel Targeting Mechanism. , 2015, Molecular therapy : the journal of the American Society of Gene Therapy.

[4]  Pengfei Cai,et al.  A Deep Analysis of the Small Non-Coding RNA Population in Schistosoma japonicum Eggs , 2013, PloS one.

[5]  Lisa Fish,et al.  Endogenous tRNA-Derived Fragments Suppress Breast Cancer Progression via YBX1 Displacement , 2015, Cell.

[6]  Yi Jing,et al.  Dissecting tRNA-derived fragment complexities using personalized transcriptomes reveals novel fragment classes and unexpected dependencies , 2015, Oncotarget.

[7]  Hui Zhou,et al.  Deep Sequencing of Human Nuclear and Cytoplasmic Small RNAs Reveals an Unexpectedly Complex Subcellular Distribution of miRNAs and tRNA 3′ Trailers , 2010, PloS one.

[8]  A. Sandelin,et al.  Hidden layers of human small RNAs , 2008, BMC Genomics.

[9]  J. Steitz,et al.  The Noncoding RNA Revolution—Trashing Old Rules to Forge New Ones , 2014, Cell.

[10]  Identification of stable, high copy number, medium-sized RNA degradation intermediates that accumulate in plants under non-stress conditions , 2013, Plant Molecular Biology.

[11]  Robert Blelloch,et al.  Mouse ES cells express endogenous shRNAs, siRNAs, and other Microprocessor-independent, Dicer-dependent small RNAs. , 2008, Genes & development.

[12]  Thurston H. Y. Dang,et al.  The human Piwi protein Hiwi2 associates with tRNA-derived piRNAs in somatic cells , 2014, Nucleic acids research.

[13]  N. Polacek,et al.  Slicing tRNAs to boost functional ncRNA diversity , 2013, RNA biology.

[14]  Pankaj Kumar,et al.  tRFdb: a database for transfer RNA fragments , 2014, Nucleic Acids Res..

[15]  Yan Guo,et al.  Mining diverse small RNA species in the deep transcriptome. , 2015, Trends in biochemical sciences.

[16]  T. Speed,et al.  A Tetrahymena Piwi bound to mature tRNA 3' fragments activates the exonuclease Xrn2 for RNA processing in the nucleus. , 2012, Molecular cell.

[17]  R. Dean,et al.  Diverse and tissue-enriched small RNAs in the plant pathogenic fungus, Magnaporthe oryzae , 2011, BMC Genomics.

[18]  Mark Helm,et al.  Post-transcriptional nucleotide modification and alternative folding of RNA , 2006, Nucleic acids research.

[19]  Daniel Gautheret,et al.  Genome-wide discovery and analysis of microRNAs and other small RNAs from rice embryogenic callus , 2011, RNA biology.

[20]  D. Haussecker,et al.  Human tRNA-derived small RNAs in the global regulation of RNA silencing. , 2010, RNA.

[21]  Michael T. McManus,et al.  Pervasive Transcription of the Human Genome Produces Thousands of Previously Unidentified Long Intergenic Noncoding RNAs , 2013, PLoS genetics.

[22]  Po-Jung Huang,et al.  A Comprehensive Expression Profile of MicroRNAs and Other Classes of Non-Coding Small RNAs in Barley Under Phosphorous-Deficient and -Sufficient Conditions , 2012, DNA research : an international journal for rapid publication of reports on genes and genomes.

[23]  B. Berkhout,et al.  A miRNA-tRNA mix-up: tRNA origin of proposed miRNA. , 2010, RNA biology.

[24]  Anita Marchfelder,et al.  High throughput sequencing reveals a plethora of small RNAs including tRNA derived fragments in Haloferax volcanii , 2012, RNA biology.

[25]  Jordan Anaya,et al.  Meta-analysis of tRNA derived RNA fragments reveals that they are evolutionarily conserved and associate with AGO proteins to recognize specific RNA targets , 2014, BMC Biology.

[26]  Markus Glatzel,et al.  CLP1 links tRNA metabolism to progressive motor-neuron loss , 2013, Nature.

[27]  A. Abdelfattah,et al.  Update on non-canonical microRNAs , 2014, Biomolecular concepts.

[28]  Wei Li,et al.  A novel class of tRNA-derived small RNAs extremely enriched in mature mouse sperm , 2012, Cell Research.

[29]  Ya-Ming Hou,et al.  CCA addition to tRNA: Implications for tRNA quality control , 2010, IUBMB life.

[30]  Tingming Liang,et al.  Cross-Mapping Events in miRNAs Reveal Potential miRNA-Mimics and Evolutionary Implications , 2011, PloS one.

[31]  W. de Souza,et al.  Gene Expression Changes Induced by Trypanosoma cruzi Shed Microvesicles in Mammalian Host Cells: Relevance of tRNA-Derived Halves , 2014, BioMed research international.

[32]  David I. K. Martin,et al.  5′ tRNA halves are present as abundant complexes in serum, concentrated in blood cells, and modulated by aging and calorie restriction , 2013, BMC Genomics.

[33]  S. Goldenberg,et al.  A population of tRNA-derived small RNAs is actively produced in Trypanosoma cruzi and recruited to specific cytoplasmic granules. , 2010, Molecular and biochemical parasitology.

[34]  H. Buermans,et al.  Deep sequencing of RNA from immune cell-derived vesicles uncovers the selective incorporation of small non-coding RNA biotypes with potential regulatory functions , 2012, Nucleic acids research.

[35]  Pamela J Green,et al.  tRNA cleavage is a conserved response to oxidative stress in eukaryotes. , 2008, RNA.

[36]  S. Yamasaki,et al.  Angiogenin cleaves tRNA and promotes stress-induced translational repression , 2009, The Journal of cell biology.

[37]  S. Le,et al.  Pyrosequencing of small non-coding RNAs in HIV-1 infected cells: evidence for the processing of a viral-cellular double-stranded RNA hybrid , 2009, Nucleic acids research.

[38]  L. Goff,et al.  Ago2 Immunoprecipitation Identifies Predicted MicroRNAs in Human Embryonic Stem Cells and Neural Precursors , 2009, PloS one.

[39]  Li-Ching Hsieh,et al.  Abundance of tRNA-derived small RNAs in phosphate-starved Arabidopsis roots , 2010, Plant signaling & behavior.

[40]  Lianbo Yu,et al.  Breast Cancer–Specific miR Signature Unique to Extracellular Vesicles Includes “microRNA-like” tRNA Fragments , 2015, Molecular Cancer Research.

[41]  Weixiong Zhang,et al.  Noncanonical microRNAs and endogenous siRNAs in normal and psoriatic human skin. , 2013, Human molecular genetics.

[42]  G. Hutvagner,et al.  Transfer RNA‐derived fragments: origins, processing, and functions , 2011, Wiley interdisciplinary reviews. RNA.

[43]  Rogerio Margis,et al.  Description of plant tRNA-derived RNA fragments (tRFs) associated with argonaute and identification of their putative targets , 2013, Biology Direct.

[44]  P. Myler,et al.  Small RNAs derived from tRNAs and rRNAs are highly enriched in exosomes from both old and new world Leishmania providing evidence for conserved exosomal RNA Packaging , 2015, BMC Genomics.

[45]  Profiling of the small RNA populations in human testicular germ cell tumors shows global loss of piRNAs , 2015, Molecular Cancer.

[46]  R. Gregory,et al.  MicroRNA biogenesis pathways in cancer , 2015, Nature Reviews Cancer.

[47]  D. Ingber,et al.  New role for tRNA and its fragment purified from human urinary bladder carcinoma conditioned medium: Inhibition of endothelial cell growth , 1999, Journal of cellular biochemistry.

[48]  G. Barton,et al.  Filtering of deep sequencing data reveals the existence of abundant Dicer-dependent small RNAs derived from tRNAs. , 2009, RNA.

[49]  Andrea Califano,et al.  tRNA-derived microRNA modulates proliferation and the DNA damage response and is down-regulated in B cell lymphoma , 2013, Proceedings of the National Academy of Sciences.

[50]  Praveen Sethupathy,et al.  Small tRNA-derived RNAs are increased and more abundant than microRNAs in chronic hepatitis B and C , 2015, Scientific Reports.

[51]  P. Zamore,et al.  Small silencing RNAs: an expanding universe , 2009, Nature Reviews Genetics.

[52]  Masaru Tomita,et al.  Precise mapping and dynamics of tRNA-derived fragments (tRFs) in the development of Triops cancriformis (tadpole shrimp) , 2015, BMC Genetics.

[53]  Computational analysis, biochemical purification, and detection of tRNA-derived small RNA fragments. , 2014, Methods in molecular biology.

[54]  G. Storz,et al.  Regulation by small RNAs in bacteria: expanding frontiers. , 2011, Molecular cell.

[55]  H. Masaki,et al.  A cytotoxic ribonuclease which specifically cleaves four isoaccepting arginine tRNAs at their anticodon loops. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[56]  N. Hayward,et al.  Characterization of the Melanoma miRNAome by Deep Sequencing , 2010, PloS one.

[57]  Andrey Grigoriev,et al.  Age-driven modulation of tRNA-derived fragments in Drosophila and their potential targets , 2015, Biology Direct.

[58]  Yi Tie,et al.  Stress induces tRNA cleavage by angiogenin in mammalian cells , 2009, FEBS letters.

[59]  N. Polacek,et al.  tRNA-Derived Fragments Target the Ribosome and Function as Regulatory Non-Coding RNA in Haloferax volcanii , 2012, Archaea.

[60]  Yuan Chang,et al.  Extensive terminal and asymmetric processing of small RNAs from rRNAs, snoRNAs, snRNAs, and tRNAs , 2012, Nucleic acids research.

[61]  Lu Wang,et al.  A novel class of heat-responsive small RNAs derived from the chloroplast genome of Chinese cabbage (Brassica rapa) , 2011, BMC Genomics.

[62]  J. Y. Chen,et al.  Isolation of a temperature-sensitive mutant with an altered tRNA nucleotidyltransferase and cloning of the gene encoding tRNA nucleotidyltransferase in the yeast Saccharomyces cerevisiae. , 1990, The Journal of biological chemistry.

[63]  S. Whisson,et al.  Fragmentation of tRNA in Phytophthora infestans asexual life cycle stages and during host plant infection , 2014, BMC Microbiology.

[64]  C. Bracken,et al.  Assessing the gene regulatory properties of Argonaute-bound small RNAs of diverse genomic origin , 2014, Nucleic acids research.

[65]  A. Malhotra,et al.  A novel class of small RNAs: tRNA-derived RNA fragments (tRFs). , 2009, Genes & development.

[66]  S. Goldenberg,et al.  Distinct subcellular localization of tRNA-derived fragments in the infective metacyclic forms of Trypanosoma cruzi. , 2012, Memorias do Instituto Oswaldo Cruz.

[67]  H. Masaki,et al.  A cytotoxic ribonuclease targeting specific transfer RNA anticodons. , 1999, Science.

[68]  B. Cullen,et al.  Derivation and characterization of Dicer- and microRNA-deficient human cells , 2014, RNA.

[69]  M. Tewari,et al.  Exosomes in human semen carry a distinctive repertoire of small non-coding RNAs with potential regulatory functions , 2014, Nucleic acids research.

[70]  K. Collins,et al.  Starvation-induced Cleavage of the tRNA Anticodon Loop in Tetrahymena thermophila* , 2005, Journal of Biological Chemistry.

[71]  Jernej Ule,et al.  Aberrant methylation of tRNAs links cellular stress to neuro-developmental disorders , 2014, The EMBO journal.

[72]  R. Parker,et al.  The RNase Rny1p cleaves tRNAs and promotes cell death during oxidative stress in Saccharomyces cerevisiae , 2009, The Journal of cell biology.

[73]  Yongfeng Jin,et al.  RIP-seq of BmAgo2-associated small RNAs reveal various types of small non-coding RNAs in the silkworm, Bombyx mori , 2013, BMC Genomics.

[74]  Yan Li,et al.  Both endo-siRNAs and tRNA-derived small RNAs are involved in the differentiation of primitive eukaryote Giardia lamblia , 2014, Proceedings of the National Academy of Sciences.

[75]  Noah Spies,et al.  Tramp-mediated Rna Surveillance Prevents Spurious Entry of Rnas into the Schizosaccharomyces Pombe Sirna Pathway Nih Public Access Author Manuscript Gene-specific Srnas Methods Fission Yeast Strains and Plasmids Generation of Small Rna Libraries for 454 Deep Sequencing Supplementary Material Acknowl , 2022 .

[76]  C. Print,et al.  Links between the Oncoprotein YB-1 and Small Non-Coding RNAs in Breast Cancer , 2013, PloS one.

[77]  Joo‐Hang Kim,et al.  Identification and clinical implications of circulating microRNAs for estrogen receptor-positive breast cancer , 2014, Tumor Biology.

[78]  Tomohiro Miyoshi,et al.  Many ways to generate microRNA-like small RNAs: non-canonical pathways for microRNA production , 2010, Molecular Genetics and Genomics.

[79]  G. Kaufmann Anticodon nucleases. , 2000, Trends in biochemical sciences.

[80]  G. Hutvagner,et al.  Small RNAs derived from the 5′ end of tRNA can inhibit protein translation in human cells , 2013, RNA biology.

[81]  A. Cayota,et al.  A particular set of small non-coding RNAs is bound to the distinctive Argonaute protein of Trypanosoma cruzi: insights from RNA-interference deficient organisms. , 2014, Gene.

[82]  Hong Li Complexes of tRNA and maturation enzymes: shaping up for translation. , 2007, Current opinion in structural biology.

[83]  T. Yoshihisa Handling tRNA introns, archaeal way and eukaryotic way , 2014, Front. Genet..