Transfer RNA-derived small RNAs (tsRNAs) are a class of small non-coding RNAs (sncRNAs) generated from precursor or mature tRNAs through specific cleavage by ribonucleases such as Angiogenin (ANG), Dicer, and RNase Z [1,4]. Once regarded as random degradation products, tsRNAs are now recognized as critical regulators of gene expression, with significant roles in physiological and pathological processes, including cancer, cardiovascular diseases, and digestive tract disorders [1-3,8].
Classification of tsRNAs
tsRNAs are broadly categorized into two main groups based on their cleavage sites:
- Produced by cleavage within the mature tRNA sequence, further subdivided into:
- tRF-5 (derived from the 5’-end of tRNA)
- tRF-3 (derived from the 3’-end of tRNA)
- tRF-1 (generated from the 3’-trailer sequence of precursor tRNA) [4,6]
- tRNA halves (tiRNAs)
Typically 30–50 nucleotides in length, generated by cleavage in the anticodon loop under stress conditions [1,5].
Biological Functions of tsRNAs
1. Gene Regulation
tsRNAs influence gene expression by:
- Acting as microRNA (miRNA)-like molecules to silence target mRNAs [7].
- Interacting with Argonaute (AGO) proteins to form RNA-induced silencing complexes (RISC) [4].
- Regulating translation by binding to ribosomal subunits [5].
2. Cellular Stress Response
tsRNAs are induced under oxidative stress, hypoxia, and nutrient deprivation, promoting cell survival or apoptosis depending on cellular context [1,6].
3. Epigenetic Regulation
Some tsRNAs influence DNA methylation and histone modifications, contributing to epigenetic reprogramming in diseases such as cancer [8].
Roles of tsRNAs in Human Diseases
1. Cancer
tsRNAs exhibit dual roles as oncogenes or tumor suppressors:
- tRF-3019A promotes gastric cancer progression by suppressing tumor suppressor genes [8].
- tRF-5026A inhibits metastasis in colorectal cancer by regulating cell migration pathways [1].
- Dysregulated tsRNAs serve as potential biomarkers for early cancer detection [8].
2. Cardiovascular Diseases
- tsRNA-000794 is upregulated in heart failure and regulates cardiomyocyte apoptosis [3].
- tRF-3-U modulates endothelial dysfunction in atherosclerosis [3].
3. Digestive Tract Diseases
- tRF3-IleAAT is associated with inflammatory bowel disease (IBD) progression [2].
- tiRNA-GlyGCC regulates gut microbiota homeostasis, influencing colitis development [2].
tsRNA Detection and Research Applications
With their diagnostic and therapeutic potential, tsRNA profiling has become a focus in molecular research. High-throughput small RNA sequencing and bioinformatics pipelines now allow:
- Comprehensive tRF and tiRNA identification
- Quantification of disease-associated tsRNA expression
- Biomarker discovery for liquid biopsy applications
Recommended Services:
- tsRNA Sequencing Services – From RNA extraction to bioinformatics analysis, covering all tRF and tiRNA subtypes.
- Custom tsRNA Functional Studies – Including in vitro transfection, RNA pull-down assays, and AGO immunoprecipitation.
- tsRNA Biomarker Development – For cancer, cardiovascular, and inflammatory diseases.
tRNA Modification Analysis Services
tRNA m5C Methylation Sequencing
tRNA m7G Modification Sequencing
Therapeutic Potential of tsRNAs
Given their regulatory functions, tsRNAs hold promise as novel therapeutic targets:
- Synthetic tsRNA mimics can restore normal gene expression in cancer [8].
- Antisense oligonucleotides (ASOs) targeting pathogenic tsRNAs may treat cardiovascular disorders [3].
- tsRNA-based liquid biopsies enable non-invasive disease monitoring [2,8].
Conclusion
tRNA-derived small RNAs are no longer considered byproducts of RNA degradation but key regulatory molecules with profound implications in disease biology. Advances in tsRNA detection technologies and functional assays are accelerating their translation into clinical applications. Leveraging tsRNA sequencing, biomarker discovery, and therapeutic targeting will open new avenues for diagnostics, treatment, and precision medicine.
References
- Emerging roles of tRNA-derived small RNAs in cancer biology Experimental & Molecular Medicine 2023 DOI: 10.1038/s12276-023-01038-5
- tRNA-derived small RNAs in digestive tract diseases: Progress and perspectives Genes & Diseases 2024 DOI: 10.1016/j.gendis.2024.101326
- The function of tRNA-derived small RNAs in cardiovascular diseases Molecular Therapy – Nucleic Acids 2024 DOI: 10.1016/j.omtn.2024.102114
- Novel insights into the roles of tRNA-derived small RNAs RNA Biology 2021 DOI: 10.1080/15476286.2021.1922009
- Emerging functional principles of tRNA-derived small RNAs and other regulatory small RNAs Journal of Biological Chemistry 2023 DOI: 10.1016/j.jbc.2023.105225
- Deciphering the tRNA-derived small RNAs: origin, development, and future Cell Death & Disease 2021 DOI: 10.1038/s41419-021-04472-3
- Transfer RNA-Derived Small RNAs: Another Layer of Gene Regulation and Novel Targets for Disease Therapeutics Molecular Therapy 2020 DOI: 10.1016/j.ymthe.2020.09.013
- tRNA-derived small RNAs in human cancers: roles, mechanisms, and clinical application Molecular Cancer 2024 DOI: 10.1186/s12943-024-01992-2