Transfer RNA-derived small RNAs in tumor microenvironment

Abstract

Transfer RNAs (tRNAs) are a class of non-coding RNAs responsible for amino acid translocation during protein synthesis and are ubiquitously found in organisms. With certain modifications and under specific conditions, tRNAs can be sheared and fragmented into small non-coding RNAs, also known as tRNA-derived small RNAs (tDRs). With the development of high-throughput sequencing technologies and bioinformatic strategies, more and more tDRs have been identified and their functions in organisms have been characterized. tRNA and it derived tDRs, have been shown to be essential not only for transcription and translation, but also for regulating cell proliferation, apoptosis, metastasis, and immunity. Aberrant expression of tDRs is associated with a wide range of human diseases, especially with tumorigenesis and tumor progression. The tumor microenvironment (TME) is a complex ecosystem consisting of various cellular and cell-free components that are mutually compatible with the tumor. It has been shown that tDRs regulate the TME by regulating cancer stem cells, immunity, energy metabolism, epithelial mesenchymal transition, and extracellular matrix remodeling, playing a pro-tumor or tumor suppressor role. In this review, the biogenesis, classification, and function of tDRs, as well as their effects on the TME and the clinical application prospects will be summarized and discussed based on up to date available knowledge.

Keywords: Biomarkers; Therapeutic; Transfer RNAs; Tumor microenvironment (TME); tRFs; tRNA-derived small RNAs (tDRs); tiRNAs.

Fig. 1

Biogenesis and classification of tDRs. During tRNA maturation, the 3’-trailer sequences are removed from pre-tRNA by the endonuclease Z (RNase Z/ELAC2), which results in the production of tRF-1. tiRNAs are generated by ANG cleavage of the anticodon loop of mature tRNAs under stressful conditions, including 5’-tiRNAs and 3’-tiRNAs. tRF-3 originates from the cleavage of the 3' end of the mature tRNA TѰC loop by Dicer or ANG. tRF-5 is cleaved in a Dicer-dependent manner in the D-loop or stem region of mature tRNA. Their subtypes are determined by the size and cleavage locations. i-tRFs are produced from the internal region of tRNAs, and can be classified into three types: D-tRF, A-tRF, and V-tRF, according to different cleavage regions

Fig. 2

The working pattern of tDRs. Transfer RNA-derived small RNAs (tDRs) can regulate gene expression at multiple levels. In the nucleus, for example, AS‑tDR‑007333 interacts with HSPB1 protein that epigenetically augments MED29 transcription. td-piR (Glu), another tDR can recruit H3K9 methyltransferases (SETDB1 and SUV39H1) to the CD1A promoter region promoter region through binding PIWIL4 protein to form a complex, resulting in CD1A transcription inhibition. In the cytoplasm, tRF-3 s can interact with AGO proteins to induce the formation of silencing complexes (RISC) or act as protein decoy to isolate the binding of RBPs (YBX1 and IGF2BP1), thereby regulating mRNA stability at the post-transcriptional level. tiRNAs with the TOG motifs, assisted by YBX1, can inhibit the translation of target mRNA by substituting eIF4F complex and inducing SG assembly. tRFs can also bind two ribosomal protein (RPS28/RPS15) mRNAs to enhance their translation and regulate ribosome biogenesis. tRF-3 s can also promote reverse transcription by targeting the primer binding site (PBS) of the HTLV-1 in viral particles