Small Noncoding RNAs in Knee Osteoarthritis: The Role of MicroRNAs and tRNA-Derived Fragments.

Knee osteoarthritis (OA) is a degenerative knee joint disease that results from the breakdown of joint cartilage and underlying bone, affecting about 3.3% of the world's population. As OA is a multifactorial disease, the underlying pathological process is closely associated with genetic changes in articular cartilage and bone. Many studies have focused on the role of small noncoding RNAs in OA and identified numbers of microRNAs that play important roles in regulating bone and cartilage homeostasis. The connection between other types of small noncoding RNAs, especially tRNA-derived fragments and knee osteoarthritis is still elusive. The observation that there is limited information about small RNAs different than miRNAs in knee OA was very surprising to us, especially given the fact that tRNA fragments are known to participate in a plethora of human diseases and a portion of them are even more abundant than miRNAs. Inspired by these findings, in this review we have summarized the possible involvement of microRNAs and tRNA-derived fragments in the pathology of knee osteoarthritis.

A tRNA-derived fragment competes with mRNA for ribosome binding and regulates translation during stress.

Posttranscriptional processing of RNA molecules is a common strategy to enlarge the structural and functional repertoire of RNomes observed in all 3 domains of life. Fragmentation of RNA molecules of basically all functional classes has been reported to yield smaller non-protein coding RNAs (ncRNAs) that typically possess different roles compared with their parental transcripts. Here we show that a valine tRNA-derived fragment (Val-tRF) that is produced under certain stress conditions in the halophilic archaeon Haloferax volcanii is capable of binding to the small ribosomal subunit. As a consequence of Val-tRF binding mRNA is displaced from the initiation complex which results in global translation attenuation in vivo and in vitro. The fact that the archaeal Val-tRF also inhibits eukaryal as well as bacterial protein biosynthesis implies a functionally conserved mode of action. While tRFs and tRNA halves have been amply identified in recent RNA-seq project, Val-tRF described herein represents one of the first functionally characterized tRNA processing products to date.

[RNA processing - unusual mechanism of generation of novel classes of noncoding RNAs from functional RNAs]. / Przetwarzanie RNA - niezwykly mechanizm powstawania nowych klas niekodujacych RNA z funkejonalnych RNA.

Non-coding RNAs (ncRNAs) play regulatory roles at all stages of the genetic information transmission from DNA to proteins. The ncRNA-mediated mechanisms leading to specific expression or silencing of particular genes seem to be of special importance. In addition to well-known and well-understood functions of RNAs, we recently discover new and nonobvious aspects and possibilities of regulating cellular processes. One example is the processing of various RNAs, the mechanism of formation of short non-coding RNAs from existing functional RNAs. Both: the sources of these short RNAs and the functions performed by them are diverse. Their presence greatly enriches the possibilities of gene expression regulation, as it turns out, at all stages.

Levels of sdRNAs in cytoplasm and their association with ribosomes are dependent upon stress conditions but independent from snoRNA expression.

In recent years, a number of small RNA molecules derived from snoRNAs have been observed. Findings concerning the functions of snoRNA-derived small RNAs (sdRNAs) in cells are limited primarily to their involvement in microRNA pathways. However, similar molecules have been observed in Saccharomyces cerevisiae, which is an organism lacking miRNA machinery. Here we examined the subcellular localization of sdRNAs in yeast. Our findings reveal that both sdRNAs and their precursors, snoRNAs, are present in the cytoplasm at levels dependent upon stress conditions. Moreover, both sdRNAs and snoRNAs may interact with translating ribosomes in a stress-dependent manner. Likely consequential to their ribosome association and protein synthesis suppression features, yeast sdRNAs may exert inhibitory activity on translation. Observed levels of sdRNAs and snoRNAs in the cytoplasm and their apparent presence in the ribosomal fractions suggest independent regulation of these molecules by yet unknown factors.

Transfer RNA-derived fragments target and regulate ribosome-associated aminoacyl-transfer RNA synthetases.

Ribosome-associated noncoding (ranc) RNAs are a novel class of short regulatory RNAs with functions and origins that have not been well studied. In this present study, we functionally characterized the molecular activity of Saccharomyces cerevisiae transfer RNA (tRNA)-derived fragments (tRFs) during protein biosynthesis. Our results indicate ribosome-associated tRFs derived from both 5' (ranc-5'-tRFs) and 3'-part of tRNAs (ranc-3'-tRFs) have regulatory roles during translation. We demonstrated five 3'-tRFs and one 5'-tRF associate with a small ribosomal subunit and aminoacyl-tRNA synthetases (aa-RSs) in yeast. Furthermore, we discovered that four yeast aa-RSs interact directly with yeast ribosomes. tRFs interactions with ribosome-associated aa-RSs correlate with impaired efficiency of tRNA aminoacylation.

When small RNAs become smaller: emerging functions of snoRNAs and their derivatives.

Small nucleolar RNAs (snoRNAs) are molecules located in the cell nucleolus and in Cajal bodies. Many scientific reports show that snoRNAs are not only responsible for modifications of other RNAs but also fulfill multiple other functions such as metabolic stress regulation or modulation of alternative splicing. Full-length snoRNAs as well as small RNAs derived from snoRNAs have been implied in human diseases such as cancer or Prader-Willi Syndrome. In this review we describe emerging, non-canonical roles of snoRNAs and their derivatives with the emphasis on their role in human diseases.

The widespread occurrence of tRNA-derived fragments in Saccharomyces cerevisiae.

Short RNAs derived from the cleavage of tRNA molecules are observed in most organisms. Their occurrence seems to be induced by stress conditions, but still little is known about their biogenesis and functions. We find that the recovery of tRNA fragments depends on the RNA isolation method. Using an optimized RNA extraction protocol and northern blot hybridization technique, we show that the tRNA-derived fragments in yeast are widespread in 12 different growth conditions. We did not observe significant stress-dependent changes in the amounts of tRNA fragments pool. Instead, we show the differential processing of almost all individual tRNAs. We also provide evidence that 3'-part-derived tRNA fragments are as abundant as the 5'- one in Saccharomyces cerevisiae. The resulting set of S. cerevisiae tRNA fragments provides a robust basis for further experimental studies on biological functions of tRFs.

Ex-translational function of tRNAs and their fragments in cancer.

Transfer RNA (tRNA) molecules are most commonly known as the molecular amino acids carriers and also because of the role they play in a protein biosynthesis process. However, tRNA biology has revealed stupendous levels of many unexpected discoveries that put a new light on tRNA function in different processes besides translation, like apoptosis or cancer development. In recent years various species of RNAs have been found differentially expressed in different types of cancer. In this review we focus our attention on tRNAs as well as on tRNA-derived small RNAs ex-translational functions in human cells in oncogenesis and oncobiology.