Modulation of mammalian translation by a ribosome-associated tRNA half

Abstract

Originally considered futile degradation products, tRNA-derived RNA fragments (tdRs) have been shown over the recent past to be crucial players in orchestrating various cellular functions. Unlike other small non-coding RNA (ncRNA) classes, tdRs possess a multifaceted functional repertoire ranging from regulating transcription, apoptosis, RNA interference, ribosome biogenesis to controlling translation efficiency. A subset of the latter tdRs has been shown to directly target the ribosome, the central molecular machine of protein biosynthesis. Here we describe the function of the mammalian tRNA Pro 5ʹ half, a 35 residue long ncRNA associated with ribosomes and polysomes in several mammalian cell lines. Addition of tRNA Pro halves to mammalian in vitro translation systems results in global translation inhibition and concomitantly causes the upregulation of a specific low molecular weight translational product. This tRNA Pro 5ʹ half-dependent translation product consists of both RNA and amino acids. Transfection of the tRNA Pro half into HeLa cells leads to the formation of the same product in vivo. The migration of this product in acidic gels, the insensitivity to copper sulphate treatment, the resistance to 3ʹ polyadenylation, and the association with 80S monosomes indicate that the accumulated product is peptidyl-tRNA. Our data thus suggest that binding of the tRNA Pro 5ʹ half to the ribosome leads to ribosome stalling and to the formation of peptidyl-tRNA. Our findings revealed a so far unknown functional role of a tdR thus further enlarging the functional heterogeneity of this emerging class of ribo-regulators.

Hijacking tRNAs From Translation: Regulatory Functions of tRNAs in Mammalian Cell Physiology

“…5 -tiRNA Ala/Cys possess a unique oligoguanine motif at their 5 terminus, which forms G-quadruplex (G4) structures required for translation inhibition (Ivanov et al, 2014). On the other hand, tsRNAs can directly interact with the ribosomes and inhibit global protein synthesis in various organisms (Gebetsberger et al, 2012;Sobala and Hutvagner, 2013;Gonskikh et al, 2020). A recent study suggests that 5 -tiRNA Pro , produced in a stress-independent manner, represses global protein synthesis through binding to the ribosomes in mammalian cells (Gonskikh et al, 2020;Figure 5).…”

“…On the other hand, tsRNAs can directly interact with the ribosomes and inhibit global protein synthesis in various organisms (Gebetsberger et al, 2012;Sobala and Hutvagner, 2013;Gonskikh et al, 2020). A recent study suggests that 5 -tiRNA Pro , produced in a stress-independent manner, represses global protein synthesis through binding to the ribosomes in mammalian cells (Gonskikh et al, 2020;Figure 5). Interestingly, addition of 5 -tiRNA Pro leads to accumulation of peptidyl-tRNA inside the arrested ribosomes (Gonskikh et al, 2020; Figure 5).…”

Non-Coding RNAs as Sensors of Oxidative Stress in Neurodegenerative Diseases

“…Furthermore, tRFs repress translation through binding to ribosomal factors, emphasizing their implication in multiple layers of gene expression regulation [91]. Specific tiRNAs, derived from tRNA-Ala and tRNA-Cys, have been shown to inhibit protein translation by assembling into a G-quadruplex-like structure (G4-motif).…”

tRNA-Derived Fragments (tRFs) in Bladder Cancer: Increased 5′-tRF-LysCTT Results in Disease Early Progression and Patients’ Poor Treatment Outcome

“…A growing body of evidence indicates that tRFs can bind to Ago and Piwi proteins and act in a miRNA-and piRNA-like manner, regulating gene expression and RNA processing. In this regard, tRFs have been implicated in a growing number of biological activities, including cell proliferation, apoptosis and homeostasis [23][24][25][26], and thus in the establishment of several human malignancies [27,28], while their utility as a novel class of molecular cancer markers has been already highlighted in breast [29], clear cell renal cell [30], colorectal [31] and prostate cancer [32].…”