tRNA-Derived Fragments Target the Ribosome and Function as Regulatory Non-Coding RNA inHaloferax volcanii

Abstract

Nonprotein coding RNA (ncRNA) molecules have been recognized recently as major contributors to regulatory networks in controlling gene expression in a highly efficient manner. These RNAs either originate from their individual transcription units or are processing products from longer precursor RNAs. For example, tRNA-derived fragments (tRFs) have been identified in all domains of life and represent a growing, yet functionally poorly understood, class of ncRNA candidates. Here we present evidence that tRFs from the halophilic archaeon Haloferax volcanii directly bind to ribosomes. In the presented genomic screen of the ribosome-associated RNome, a 26-residue-long fragment originating from the 5′ part of valine tRNA was by far the most abundant tRF. The Val-tRF is processed in a stress-dependent manner and was found to primarily target the small ribosomal subunit in vitro and in vivo. As a consequence of ribosome binding, Val-tRF reduces protein synthesis by interfering with peptidyl transferase activity. Therefore this tRF functions as ribosome-bound small ncRNA capable of regulating gene expression in H. volcanii under environmental stress conditions probably by fine tuning the rate of protein production.

Slicing tRNAs to boost functional ncRNA diversity

“…57 These differences in tRNA specificities, abundance, and length support the conclusion that distinct biogenesis mechanisms are at work.…”

“…18 A markedly different cellular function for 5′ tRFs has been very recently proposed. 57 In the archaeon Haloferax volcanii, a 26 nt-long tRF originating from tRNA…”

“…Even though 5′ tRNA halves also repress protein biosynthesis (see above), 52 the mechanisms clearly differ: (1) the proposed terminal oligo-G motif of 5′ tRNA halves is either absent in the investigated 5′ tRFs or not crucial for the inhibitory potential, (2) 5′ tRFs do not target mRNA, (3) whereas 5′ halves associate with translation initiation factors and the translational silencer protein YB-1, 5′ tRFs associate with ribosomal particles (30S ribosomal subunits and polysomes in H. volcanii; polysomes, and RNPs smaller than 40S subunits in human cells). 57,64 How exactly these 5′ tRFs perform their action on the ribosome, and how they are processed awaits experimental clarification.…”

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

“…The same study also reported that the 5Ј-terminal oligoguanine sequence is essential for the translational repression ability of these tiRNAs (23). The translation inhibitory effect of tRNA fragments has been also reported in other organisms; the 26-nucleotide 5Ј-tRFs derived from tRNA Val have been shown to inhibit translation in the archaeon Haloferax volcanii (24). Similar to tiRNAs, Val-tRF is produced in a stress-dependent manner.…”

The multifaceted regulatory potential of tRNA-derived fragments

“…First, they are not restricted to one domain of life since they have been found in archaea, bacteria as well as in uni-and multicellular eukarya. Second, the biological roles of tdRs embrace regulation of transcription (6), translation (5,(7)(8)(9), stress granule formation (10), apoptosis (11), cell proliferation (12,13), RNAi (14), vesicle-mediated intercellular communication (6), and intergenerational inheritance (15) (Figure 1). Therefore, the mere detection of a tRNA fragment in a deep-sequencing screen does not allow reasonable deductions to be made about its biogenesis or function.…”