tRNA-derived small RNA (tsRNA or tRNA-related fragment, tRF) biogenesis

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Homo sapiens
Related Species
Human immunodeficiency virus 1
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Defined fragments of tRNAs, termed tRNA‑derived small RNAs (tsRNAs), have been observed in particular cell types and in response to biological conditions such as exposure to sex hormone or stresses such as hypoxia, starvation, oxidative stress, and virus infection (reviewed in Keam and Hutvagner 2015, Kumar et al. 2016, Oberbauer and Schaefer 2018, Park et al. 2020, Su et al. 2020, Xie et al. 2020, Zhu et al. 2020). Rather than being the random products of tRNA degradation, tsRNAs appear to be the specific products of ribonucleases. Two categories of tRNA‑derived small RNAs (tsRNAs) have been described: (1) longer (31‑40nt) tsRNAs known as tRNA halves or stress‑induced tsRNAs (tiRNAs) that are produced by single cleavage of tRNAs within or near the anticodon and (2) shorter (15‑30 nt) tsRNAs termed tRNA-related fragments (tRFs) that result from cleavage closer to the 5' or 3' end of the tRNA. tRF-3s are derived from the 3' region of the tRNA, approximately the region from the T loop to the 3' terminus. tRF-5s are derived from the 5' region of the tRNA, approximately the region from the D loop to the 5' terminus. tRF2‑type tRFs (also called internal tRFs) are derived from the central region of the tRNA, approximately the region between the D loop and the T loop and containing the anticodon. tRF-1s, also known as Type II tRFs or 3’U tRFs, are the 3' trailers of particular tRNAs that persist after processing.
In most cases the enzymes responsible for the cleavages are not yet known, however several ribonucleases involved in cleavage of tRNA have been identified: the secreted and endocytosed ribonuclease A family members angiogenin (ANG) and RNase 1; the interferon-induced ribonucleases RNase L, Schlafen 11 (SLFN11) and Schlafen13 (SLFN13 or RNase S13); the cytosolic ribonuclease III‑like (double strand RNA‑specific) enzyme DICER1; and the RNA processing enzyme ELAC2. ANG is secreted, binds receptors on cell membranes, is endocytosed, and translocates to the nucleus. ANG cleaves within the anticodon loop to produce tRNA halves and the cleavage is thought to occur while ANG is transiently located in the cytosol (Lee and Vallee 1989, Saxena et al. 1992, Fu et al. 2009, Yamasaki et al. 2009, Emara et al. 2010, Ivanov et al. 2011). Cleavage by ANG is observed in response to cellular stresses such as starvation (Fu et al. 2009, Yamasaki et al. 2009, Emara et al. 2010, Ivanov et al. 2011). However, ANG knockout cells continue to produce stress-induced tRNA halves, suggesting that other enzymes are also involved in producing the halves (Su et al. 2019). Similar to ANG as an RNase A member, the secreted endoribonuclease RNase 1 cleaves tRNAs at the anticodon loop in the extracellular space (Nechooshtan et al. 2020).
Interferon-induced RNases can also cleave tRNAs. RNase L is responsive to double stranded RNAs and cleaves at the tRNA anticodon loop (Donovan et al. 2017). Schlafen family members SLFN11 and SLFN13 can also cleave tRNAs (Li et al. 2018, Yang et al. 2018).
DICER1 cleaves double‑stranded regions of tRNAs near the 5' terminus or 3' terminus to produce short tRFs (Cole et al. 2009, Yeung et al. 2009, Maute et al. 2013, Hasler et al. 2016). The mechanism that dissociates the double‑stranded products of DICER1 to yield single‑stranded tRFs may be the same as that for miRNAs, but this has not yet been demonstrated. Furthermore, the bulk of the short tRFs is still detected in DICER1-null cells (Kumar 2014, Kuscu & Kumar et al. 2018), suggesting other unknown factors are involved in their biogenesis. ELAC2 in the cytosol cleaves the 3' trailers of precursors of tRNA Ser TGA, tRNA Ser GTC, and tRNA Asp GTC, and tRNA Asp GTC (Lee et al. 2009). The trailers (also called tRF-1s) then persist in the cytosol (Kumar et al. 2014).

Literature References
PubMed ID Title Journal Year
25270025 Meta-analysis of tRNA derived RNA fragments reveals that they are evolutionarily conserved and associate with AGO proteins to recognize specific RNA targets

Kumar, P, Anaya, J, Mudunuri, SB, Dutta, A

BMC Biol 2014
21855800 Angiogenin-induced tRNA fragments inhibit translation initiation

Ivanov, P, Emara, MM, Villén, J, Gygi, SP, Anderson, P

Mol Cell 2011
30374083 DNA damage-induced cell death relies on SLFN11-dependent cleavage of distinct type II tRNAs

Li, M, Kao, E, Malone, D, Gao, X, Wang, JYJ, David, M

Nat Struct Mol Biol 2018
23297232 tRNA-derived microRNA modulates proliferation and the DNA damage response and is down-regulated in B cell lymphoma

Maute, RL, Schneider, C, Sumazin, P, Holmes, A, Califano, A, Basso, K, Dalla-Favera, R

Proc Natl Acad Sci U S A 2013
20129916 Angiogenin-induced tRNA-derived stress-induced RNAs promote stress-induced stress granule assembly

Emara, MM, Ivanov, P, Hickman, T, Dawra, N, Tisdale, S, Kedersha, N, Hu, GF, Anderson, P

J Biol Chem 2010
29844106 tRNA fragments (tRFs) guide Ago to regulate gene expression post-transcriptionally in a Dicer-independent manner

Kuscu, C, Kumar, P, Kiran, M, Su, Z, Malik, A, Dutta, A

RNA 2018
19729508 Pyrosequencing of small non-coding RNAs in HIV-1 infected cells: evidence for the processing of a viral-cellular double-stranded RNA hybrid

Yeung, ML, Bennasser, Y, Watashi, K, Le, SY, Houzet, L, Jeang, KT

Nucleic Acids Res 2009
30563140 tRNA-Derived Small RNAs: Biogenesis, Modification, Function and Potential Impact on Human Disease Development

Oberbauer, V, Schaefer, MR

Genes (Basel) 2018
19850906 Filtering of deep sequencing data reveals the existence of abundant Dicer-dependent small RNAs derived from tRNAs

Cole, C, Sobala, A, Lu, C, Thatcher, SR, Bowman, A, Brown, JW, Green, PJ, Barton, GJ, Hutvagner, G

RNA 2009
19114040 Stress induces tRNA cleavage by angiogenin in mammalian cells

Fu, H, Feng, J, Liu, Q, Sun, F, Tie, Y, Zhu, J, Xing, R, Sun, Z, Zheng, X

FEBS Lett 2009
32606362 Action mechanisms and research methods of tRNA-derived small RNAs

Xie, Y, Yao, L, Yu, X, Ruan, Y, Li, Z, Guo, J

Signal Transduct Target Ther 2020
2730651 Characterization of ribonucleolytic activity of angiogenin towards tRNA

Lee, FS, Vallee, BL

Biochem Biophys Res Commun 1989
32992597 tRNA-Derived Small RNAs: Novel Epigenetic Regulators

Park, J, Ahn, SH, Shin, MG, Kim, HK, Chang, S

Cancers (Basel) 2020
28808124 Rapid RNase L-driven arrest of protein synthesis in the dsRNA response without degradation of translation machinery

Donovan, J, Rath, S, Kolet-Mandrikov, D, Korennykh, A

RNA 2017
27263052 Biogenesis and Function of Transfer RNA-Related Fragments (tRFs)

Kumar, P, Kuscu, C, Dutta, A

Trends Biochem Sci 2016
32609822 Processing by RNase 1 forms tRNA halves and distinct Y RNA fragments in the extracellular environment

Nechooshtan, G, Yunusov, D, Chang, K, Gingeras, TR

Nucleic Acids Res 2020
1400510 Angiogenin is a cytotoxic, tRNA-specific ribonuclease in the RNase A superfamily

Saxena, SK, Rybak, SM, Davey, RT, Youle, RJ, Ackerman, EJ

J Biol Chem 1992
19933153 A novel class of small RNAs: tRNA-derived RNA fragments (tRFs)

Lee, YS, Shibata, Y, Malhotra, A, Dutta, A

Genes Dev 2009
31582561 Angiogenin generates specific stress-induced tRNA halves and is not involved in tRF-3-mediated gene silencing

Su, Z, Kuscu, C, Malik, A, Shibata, E, Dutta, A

J Biol Chem 2019
29563550 Structure of Schlafen13 reveals a new class of tRNA/rRNA- targeting RNase engaged in translational control

Yang, JY, Deng, XY, Li, YS, Ma, XC, Feng, JX, Yu, B, Chen, Y, Luo, YL, Wang, X, Chen, ML, Fang, ZX, Zheng, FX, Li, YP, Zhong, Q, Kang, TB, Song, LB, Xu, RH, Zeng, MS, Chen, W, Zhang, H, Xie, W, Gao, S

Nat Commun 2018
32841070 Noncanonical Roles of tRNAs: tRNA Fragments and Beyond

Su, Z, Wilson, B, Kumar, P, Dutta, A

Annu Rev Genet 2020
32195016 Role of tRNA-derived fragments in cancer: novel diagnostic and therapeutic targets tRFs in cancer

Zhu, P, Yu, J, Zhou, P

Am J Cancer Res 2020
27345152 The Lupus Autoantigen La Prevents Mis-channeling of tRNA Fragments into the Human MicroRNA Pathway

Hasler, D, Lehmann, G, Murakawa, Y, Klironomos, F, Jakob, L, Grässer, FA, Rajewsky, N, Landthaler, M, Meister, G

Mol Cell 2016
26703738 tRNA-Derived Fragments (tRFs): Emerging New Roles for an Ancient RNA in the Regulation of Gene Expression

Keam, SP, Hutvagner, G

Life (Basel) 2015
19332886 Angiogenin cleaves tRNA and promotes stress-induced translational repression

Yamasaki, S, Ivanov, P, Hu, GF, Anderson, P

J Cell Biol 2009
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