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Discovery and function of transfer RNA‐derived fragments and their role in disease

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Until recently, transfer RNAs (tRNAs) were thought to function in protein translation only. However, recent findings demonstrate that both pre‐ and mature tRNAs can undergo endonucleolytic cleavage by different ribonucleases originating different types of small non‐coding RNAs, known as tRNA‐derived fragments (tRFs). tRFs are classified according to their origin and are implicated in various cellular processes, namely apoptosis, protein synthesis control, and RNA interference. Although their functions are still poorly understood, their mechanisms of action vary according to the tRF sub‐type. Several tRFs have been associated with cancer, neurodegenerative disorders, and viral infections and growing evidence shows that they may constitute novel molecular targets for modulating pathological processes. Here, we recapitulate the current knowledge of tRF biology, highlight the known functions and mechanisms of action of the different sub‐classes of tRFs and discuss their implications in human disease. WIREs RNA 2017, 8:e1423. doi: 10.1002/wrna.1423 This article is categorized under: RNA Processing > tRNA Processing Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA in Disease and Development > RNA in Disease
Diversity of transfer RNA‐derived fragments (tRFs). Different types of tRFs are produced from either the pre‐tRNA or the mature tRNA. Rnase P removes the 5′ leader of pre‐tRNA transcripts and RNase Z (ELAC2) removes the 3′ trailer. tRFs belonging to the tRF‐1 series (yellow) are produced upon cleavage of the pre‐tRNA molecule by RNAseZ (or ELAC2). The mature tRNA contains multiple modified nucleosides. Several tRFs are produced by endonucleolytic cleavage of the mature tRNAs. Dicer and angiogenin, are involved in tRF biogenesis in vertebrates. Dicer can cleave both the D‐ and T‐loop and angiogenin cleaves both near the TψC loop and the anticodon loop. Depending on their origin and composition, tRFs originated from mature tRNAs are known as tRF‐5 (blue) and tRF‐3 (red), endogenous tRFs (i‐tRFs—green), sex hormone‐dependent tRNA‐derived RNAs (SHOT‐RNAs) (purple) and tRNA halves (gray).
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Function of tRNA‐derived fragments (tRFs) and association with disease. Several cellular functions have been attributed to the different sub‐classes of tRFs, which are also implicated in cancer, neurodegenerative disorders, and infection. Functions that have been experimentally demonstrated for each type of tRF are represented, as well as the linked disease and the references. At least one member of the tRF‐1 series (yellow)—tRF‐1001 has been implicated in cellular proliferation and tRFs belonging to this class have been found deregulated in cancer. Both tRF‐5 (blue) and tRF‐3s (red) can enter the RNA interference pathway and regulate gene translation at the post‐transcriptional level, similarly to microRNAs. These tRFs have also been found deregulated in different cancers and viral infections. Endogenous tRFs (i‐tRFs) (green) and tRNA halves (gray) regulate translation by different mechanisms and are relevant in cancer and neurodegeneration contexts.
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Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs
RNA in Disease and Development > RNA in Disease
RNA Processing > tRNA Processing

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