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Trna-Derived Short Non-Coding RNA As Interacting Partners of Argonaute Proteins Thomas Jefferson University Jefferson Digital Commons Computational Medicine Center Faculty Papers Computational Medicine Center 7-9-2015 tRNA-Derived Short Non-coding RNA as Interacting Partners of Argonaute Proteins. Megumi Shigematsu Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University Yohei Kirino, PhD Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University Follow this and additional works at: https://jdc.jefferson.edu/tjucompmedctrfp Part of the Other Medical Specialties Commons Let us know how access to this document benefits ouy Recommended Citation Shigematsu, Megumi and Kirino, PhD, Yohei, "tRNA-Derived Short Non-coding RNA as Interacting Partners of Argonaute Proteins." (2015). Computational Medicine Center Faculty Papers. Paper 7. https://jdc.jefferson.edu/tjucompmedctrfp/7 This Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of Thomas Jefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarly publications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers and interested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion in Computational Medicine Center Faculty Papers by an authorized administrator of the Jefferson Digital Commons. For more information, please contact: [email protected]. tRNA-Derived Short Non-coding RNA as Interacting Partners of Argonaute Proteins Megumi Shigematsu and Yohei Kirino Computational Medicine Center, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA. ABSTR ACT: The advent of next-generation sequencing technologies has not only accelerated findings on various novel non-coding RNA (ncRNA) species but also led to the revision of the biological significance and versatility of fundamental RNA species with canonical function, such as transfer RNAs (tRNAs). Although tRNAs are best known as adapter components of translational machinery, recent studies suggest that tRNAs are not always end products but can further serve as a source for short ncRNAs. In many organisms, various tRNA-derived ncRNA species are produced from mature tRNAs or their precursor transcripts as functional molecules involved in various biological processes beyond translation. In this review, we focus on the tRNA- derived ncRNAs associated with Argonaute proteins and summarize recent studies on their conceivable biogenesis factors and on their emerging roles in gene expression regulation as regulatory RNAs. KEYWORDS: transfer RNA, tRNA fragment, microRNA, Argonaute family protein, AGO protein CITATION: Shigematsu and Kirino. tRNA-Derived Short Non-coding RNA as Interacting COpyriGHT: © the authors, publisher and licensee Libertas Academica Limited. This is Partners of Argonaute Proteins. Gene Regulation and Systems Biology 2015:9 27–33 an open-access article distributed under the terms of the Creative Commons CC-BY-NC doi: 10.4137/GRSB.S29411. 3.0 License. TYPE: Review Paper subject to independent expert blind peer review. All editorial decisions made by independent academic editor. Upon submission manuscript was subject to anti- ReceiVed: May 07, 2015. RESUBMITTed: June 28, 2015. AccepTed FOR plagiarism scanning. Prior to publication all authors have given signed confirmation of PUBLicaTION: July 09, 2015. agreement to article publication and compliance with all applicable ethical and legal AcadeMic ediTOR: James Willey, Editor in Chief requirements, including the accuracy of author and contributor information, disclosure of competing interests and funding sources, compliance with ethical requirements relating Peer REVieW: Six peer reviewers contributed to the peer review report. Reviewers’ to human and animal study participants, and compliance with any copyright requirements reports totaled 761 words, excluding any confidential comments to the academic editor. of third parties. This journal is a member of the Committee on Publication Ethics (COPE). FUndinG: Authors disclose no funding sources. Published by Libertas Academica. Learn more about this journal. COMpeTinG INTeresTS: Authors disclose no potential conflicts of interest. COrrespOndence: [email protected] Introduction fundamental adapter components of translational machinery, The advent of next-generation sequencing (NGS) technologies where they translate codons in mRNA into amino acids in has unveiled the entire picture of the cellular transcriptome, protein.14 The human genome encodes .500 tRNA genes,15 wherein various non-coding RNA (ncRNA) are widely along with numerous tRNA-lookalikes resembling nuclear expressed from a large part of the genome.1,2 The functional and mitochondrial tRNAs.16,17 The multitude of tRNA genes significance of ncRNAs is particularly evident for the short in the genome, along with high stability,18 places tRNAs 20- to 31-nucleotide (nt) ncRNAs bound to the family of among the most abundant RNA molecules in the cellular Argonaute proteins.3–5 MicroRNAs (miRNAs), the best- transcriptome. Because of their abundance and well-defined studied class of such RNAs, are approximately 22 nt in length role in translation, RNA fragments derived from tRNAs, and posttranscriptionally regulate the expression of comple- found in early NGS studies, were often disregarded as non- mentary target mRNAs. While nearly 2,800 species of human functional degradation products. However, recent biochemi- miRNAs are currently annotated in the miRBase database,6 cal and bioinformatic evidence has generated a previously computational analyses of massive RNA-sequencing (RNA- unsuspected concept that tRNAs are not always end products Seq) data has kept increasing the number of miRNA spe- but are further able to serve as a source for short ncRNAs. cies.7,8 miRNAs are estimated to regulate the expression of In many organisms, specific tRNA-derived ncRNAs are pro- most protein-coding genes,9 and a wide variety of other short duced from mature tRNAs or their precursor transcripts, not and long functional ncRNA species coexist in the cellular as random degradation products, but as functional molecules transcriptome,10,11 exhibiting a tremendous impact of ncRNA- involved in many biological processes beyond translation.19–23 orchestrated regulatory mechanisms on normal developmen- tRNA-derived ncRNAs identified to date can be classified tal and physiological processes and diseases.12,13 NGS studies into two groups: tRNA halves and tRNA-derived fragments have accelerated findings on not only novel ncRNA repertoires (tRFs).19–23 tRNA halves are composed of 30–35 nt fragments but also well-characterized fundamental RNA species with derived from either the 5′- or the 3′-part of mature tRNAs. canonical functions, such as transfer RNAs (tRNAs), which tRFs are shorter than tRNA halves, ranging from 13 to 32 nt stimulated us to revisit their significance and versatility. in length and are currently subclassified into four subgroups: tRNAs are 70- to 90-nt ncRNAs that fold into a cloverleaf 5′-tRFs, 3′-CCA tRFs, 3′-U tRFs, and 5′-leader-exon tRFs. The secondary structure and L-shaped tertiary structure. Since 5′-tRFs and 3′-CCA tRFs correspond to the 5′- and 3′-parts of their discovery in the 1950s, tRNAs have been best known as mature tRNAs containing processed mature 5′- and 3′-CCA GENE REGULATION AND SYSTEMS BIOLOGY 2015:9 27 Shigematsu and Kirino termini, respectively (Fig. 1). The ′3-U tRFs are derived from expressed in numerous tissues, and four of the PIWI clade, the 3′-leader sequence of precursor tRNAs (pre-tRNAs) that whose expressions are restricted to the germline.3–5 All harbor 3′-terminal uridine stretches, which result from tran- four AGO members associate with miRNAs to form effec- scriptional termination by RNA polyme rase III at thymidine tor complexes for their posttranscriptional regulatory roles, tracts (Fig. 1). The ′5-leader-exon tRFs include the 5′-leader while only AGO2 shows endonucleolytic cleavage activity of sequence of pre-tRNAs and the 5′-part of mature tRNAs. target mRNAs. Biochemical purification and identification Although several excellent reviews have already described the of miRNAs and their target mRNAs have been accompli- repertoire, biogenesis, and functional significance of each class shed by purifying AGO proteins using immunoprecipitation of the tRNA-derived ncRNAs,19–23 in this review, we par- (AGO-IP) followed by investigation of the AGO-bound RNAs ticularly focus on the tRFs bound to Argonaute proteins and in the IP fraction.24,25 Similar sizes of tRFs with miRNAs summarize their conceivable biogenesis factors and emerging allowed researchers to reason that tRFs may be AGO-bound roles in gene expression regulation as miRNAs. RNA species. Although early studies have already observed tRNA-derived sequences from AGO-IP fraction, as described tRFs Associated with AGO Proteins below, more recent reports have demonstrated an evident asso- In humans, the Argonaute protein family has eight members: ciation of the tRNA-derived ncRNAs with AGO proteins. four of the AGO clade (AGO1–4), which are ubiquitously Hereafter, we will use tRF amino acid/anticodon to denote a tRF RNA RNA pol II / III pol III TTTT U U UU DGCR8 Drosha RNase Z RNase P Precursor pri-miRNA tRNA o Amincid a CCA A A
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