Sayan Roy, M.Sc. Biotechnology, Pondicherry University
tRNAs are the intricate biological molecules involved in the flow of genetic information from DNA to protein by reading codons in mRNA. Besides tRNA and mRNA, several non-coding RNAs (ncRNAs) have been discovered by scientists over the past few decades that include long non-coding RNAs (lncRNAs) and small non-coding RNAs (sncRNAs).
tRNA fragments (tRFs) are tRNA-derived ncRNAs that regulate transcriptional and post-transcriptional gene expression. tRFs are precisely controlled tRNA degradation products of 14-50 nucleotides in length. There are four categories of tRFs – a) 1-TRF produced during tRNA maturation by removal of 3′-trailer sequences from pre-tRNA, b) 5′-TRF produced by 5′ end cleavage in the D-loop of mature t-RNA, c) 3′-TRF produced by 3′ end cleavage in the T-loop of mature t-RNA, d) tRNA-derived stress-induced RNAs (tiRNAs) produced by Angiogenin (ANG) mediated specific cleavage in anticodon loops of mature tRNA, under stress conditions.
tRFs are actively involved in RNA silencing, Translation regulation & Epigenetic regulation. tRFs are actively involved in various cellular processes associated with cancer development and progression. Few TRFs are differentially expressed in breast cancers which makes it a potential candidate for breast cancer diagnostic biomarkers and therapeutic targets.
It has been experimentally found that tRFs derived from tRNAGlu, tRNAAsp, tRNAGly, and tRNATyr can suppress the development of BC metastasis by binding to the oncogenic RNA-binding protein YBX1. tRF3E is a 3′-tRF derived from tRNA-GluTTC that acts as a tumor suppressor, expressed in healthy mammary glands. The degree of malignancy of breast cancer can be identified by measuring the levels of tRF3E and 5′-tiRNAVal levels in the blood and may serve as diagnostic biomarkers. tRF-1001 produced by tRNA 3′-endonuclease ELAC2, aid in the proliferation of prostate cancer cells, thus serving as an excellent biomarker. ts-101, ts-53, ts-46, and ts-47 are four tRFs that are downregulated in chronic lymphocytic leukemia (CLL) and Lung cancer. tRF-5s and tRH-5s are the most abundant tRFs in Liver cancer cells.
tRFs have great potential as therapeutic targets. tRFmimetics or antisense molecules against TRFs can be used to treat tumor progression and metastasis. The higher expression level of tRF-30-JZOYJE22RR33 and tRF-27-ZDXPHO53KSN in HER-2-positive breast cancer patients is associated with trastuzumab resistance. Similarly, tDR-0009 and tDR-7336 upregulation has facilitated doxorubicin resistance in triple-negative breast cancer cells.
With different cancer types, the expression of tRFs varies greatly. The mechanisms of carcinogenesis and progression controlled by tRFs are largely unknown. In order to identify tRFs as diagnostic and prognostic biomarkers and therapeutic targets for clinical application, further functional research is needed.
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References:
- Yu, M., Lu, B., Zhang, J. et al. tRNA-derived RNA fragments in cancer: current status and future perspectives. J Hematol Oncol 13, 121 (2020). https://doi.org/10.1186/s13045-020-00955-6
- Zhu P, Yu J, Zhou P. Role of tRNA-derived fragments in cancer: novel diagnostic and therapeutic targets tRFs in cancer. Am J Cancer Res. 2020;10(2):393-402. Published 2020 Feb 1.
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