Deciphering the tRNA-derived small RNAs: origin, development, and future

Abstract

Transfer RNA (tRNA)-derived small RNAs (tsRNAs), a novel category of small noncoding RNAs, are enzymatically cleaved from tRNAs. Previous reports have shed some light on the roles of tsRNAs in the development of human diseases. However, our knowledge about tsRNAs is still relatively lacking. In this paper, we review the biogenesis, classification, subcellular localization as well as action mechanism of tsRNAs, and discuss the association between chemical modifications of tRNAs and the production and functions of tsRNAs. Furthermore, using immunity, metabolism, and malignancy as examples, we summarize the molecular mechanisms of tsRNAs in diseases and evaluate the potential of tsRNAs as new biomarkers and therapeutic targets. At the same time, we compile and introduce several resource databases that are currently publicly available for analyzing tsRNAs. Finally, we discuss the challenges associated with research in this field and future directions.

A Synthetic Small RNA Homologous to the D-Loop Transcript of mtDNA Enhances Mitochondrial Bioenergetics

“…The SncmtRNA and ASncmtRNA exit into the cytosol, where they oppose each other to regulate the cell cycle progression and growth ( Burzio et al, 2009 ; Borgna et al, 2017 ; Farfan et al, 2021 ). There is also evidence that mitochondrion-encoded tRNA-derived small fragments exit from the mitochondria under certain conditions, including cellular stress, and participate in different signaling pathways that operate between the mitochondria and the host cell ( Liu et al, 2021 ; Meseguer, 2021 ). Two novel lncRNAs from the D-loop region were identified in the mammalian mitochondria: the H-strand transcript mitochondrial D-Loop (MDL1) and L-strand transcript MDL1AS.…”

A Non-Canonical Link between Non-Coding RNAs and Cardiovascular Diseases

“…tRNA-derived miRNAs are produced during the maturation of tRNAs, but they share functions similar to those of miRNAs, such as the silencing of RNA transcripts. First data reporting the existence of tRNA-derived miRNAs emerged from HIV infected cells showing an increased number of tRNAs of approximatively 20 nt in length deriving from the HIV-transcriptional promoter tRNA-Lys3 [ 58 , 60 ]. These tRNAs showed the ability to bind Ago2 and to act as Dicer substrate, following a duplex tRNA formation [ 58 ].…”

“…Like snoRNA-derived miRNAs, tRNA-derived miRNAs are 18–22 nt in length and derive from both the 5´and 3´ends of mature tRNAs ( Figure 1 ). Interestingly, Dicer knockout studies indicate that tRNA-derived miRNAs are more sensitive to Dicer deficiency than canonical miRNAs [ 58 , 60 ]. However, their binding to Ago proteins seems to be less stable than that of canonical miRNAs, probably due to their sensitivity to post-transcriptional modifications [ 58 , 60 ].…”

“…Interestingly, Dicer knockout studies indicate that tRNA-derived miRNAs are more sensitive to Dicer deficiency than canonical miRNAs [ 58 , 60 ]. However, their binding to Ago proteins seems to be less stable than that of canonical miRNAs, probably due to their sensitivity to post-transcriptional modifications [ 58 , 60 ]. Their function is still unknown, but few data suggest that tRNA-derived miRNAs might support miRNA biogenesis and cell proliferation [ 58 , 60 , 61 ]…”

“…As an example, tRNA CU1276 can suppress the expression of RPA1, an enzyme crucial for DNA damage repair in cancer cells [ 61 ]. In addition, as with other miRNAs, stress-induced tRNA-derived miRNA FZD3 inhibits cell proliferation by targeting members of the Wnt signalling pathway [ 60 ]. However, it is still not clear if this function is exerted through the RISC complex.…”