The Many Virtues of tRNA-derived Stress-induced RNAs (tiRNAs): Discovering Novel Mechanisms of Stress Response and Effect on Human Health

Abstract

In mammalian cells, mature tRNAs are cleaved by stress-activated ribonuclease angiogenin to generate 5-and 3-tRNA halves: a novel class of small non-coding RNAs of 30 -40 nucleotides in length. The biogenesis and biological functions of tRNA halves are emerging areas of research. This review will discuss the most recent findings on: (i) the mechanism and regulation of their biogenesis, (ii) their mechanism of action (we will specifically discuss their role in the protein synthesis inhibition and the intrinsic pathway of apoptosis), and (iii) their effects on the human physiology and disease conditions. Recent breakthroughs in high-throughput sequencing have led to a more comprehensive view of the cellular transcriptome. We are now aware of numerous additional non-protein-coding RNA (ncRNA) 3 candidates in all three domains of life, thus indicating a hidden layer of transcriptome complexity (1, 2). A more recent development in our understanding of the complexity of cellular RNomes arose with the exciting discovery that ncRNA transcripts with well described functions, such as the tRNAs, can serve as precursors for downstream cleavage events, generating yet another class of functional RNA fragments. Two major classes of tRNA fragments have been identified in human cells. The 17-26-nucleotide long tRNA-derived RNA fragments (tRFs) are products of precise processing at the 5Ј-or 3Ј-end of mature or precursor tRNAs. The tRF-5 and tRF-3 are derived from terminal ends of mature tRNAs, whereas tRF-1 are 3Ј-trailer sequences of pre-tRNAs (3). The other important class of tRNA fragments found in mammalian cells and tissues is the tRNA-derived stress-induced RNAs (tiRNAs). tiRNAs were first reported in human fetus hepatic tissue (4) and human osteosarcoma cells (U2OS), respectively (5). tRFs and tiRNAs are the newest members of the cellular ncRNA repertoire that are found in several organisms and play prominent roles in various cellular functions (6). These tRNA fragments can be generated in cells under physiological conditions and also produced as part of the cellular stress response (4 -9). In mammalian cells, tiRNAs are produced by the cleavage of mature tRNAs at positions close to the anticodon, giving rise to the 30 -40-nucleotide-long 5Ј-and 3Ј-tRNA halves, a term used interchangeably with 5Ј-and 3Ј-tiRNAs throughout this review. The enzyme responsible for this endonucleolytic cleavage is angiogenin (ANG) (4,5). ANG is a member of the pancreatic RNase superfamily distinguished by its potent in vivo angiogenic activity as well as its prominent role in cancer development and neurodegeneration (10, 11). Here we will review the ANG-induced tRNA halves (tiRNAs), their role in mammalian stress response mechanisms, and other cellular functions. Additionally, we will discuss their potential implications in the pathobiology of human diseases with a special focus on neurodegenerative disorders. ANG-induced tRNA Cleavage in Mammalian CellsEndonucleolytic cleavage of mammalian tRNAs by ANG was reported by two research groups in...

A Ribosomal Perspective on Proteostasis and Aging

“…Another way to alter the pool of available tRNAs is by inducing their endonucleolytic cleavage, which occurs under oxidative stress conditions (Thompson and Parker, 2009). tRNA cleavage events give rise to small RNA species that may function as secondary stress signals (Saikia and Hatzoglou, 2015).…”

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

“…Later on it was shown that tiRNAs inhibit protein synthesis and induce the phospho-eIF2α-independent assembly of stress granules (SGs). The stress-induced tiRs, produced independent of the sex-hormone stimulated pathways, have been implicated by others in translation repression and as anti-apopotic factors, as reviewed in [51]. …”

Long distance RNA movement

“…This could be at least in part attributed to tRNA fragments produced most likely by an RNAse processing mature amino‐acylated tRNAs in halves that are abundant in phloem exudates of pumpkin (Zhang et al ., ). Notably, translational inhibition by tRNA halves also is observed in mammalian cell cultures (Thompson & Parker, ; Yamasaki et al ., ) probably caused by interfering with mRNA access to ribosomes (Saikia & Hatzoglou, ; Gebetsberger et al ., ). In higher eukaryotes, tRNA halves are produced by RNAse T2 class RNases that hydrolyze tRNAs in their anticodon loop and play a role in tumour‐induced angiogenesis (blood vessel formation) and developmental switches, and, in most species, are part of general stress responses (Jochl et al ., ; Fu et al ., ; Thompson & Parker, ).…”