Abstract
A growing class of small RNAs, known as tRNA-derived RNAs (tdRs), tRNA-derived small RNAs or tRNA-derived fragments, have long been considered mere intermediates of tRNA degradation. These small RNAs have recently been implicated in an evolutionarily conserved repertoire of biological processes. In this Review, we discuss the biogenesis and molecular functions of tdRs in mammals, including tdR-mediated gene regulation in cell metabolism, immune responses, transgenerational inheritance, development and cancer. We also discuss the accumulation of tRNA-derived stress-induced RNAs as a distinct adaptive cellular response to pathophysiological conditions. Furthermore, we highlight new conceptual advances linking RNA modifications with tdR activities and discuss challenges in studying tdR biology in health and disease.
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Acknowledgements
We thank all the members of the Bellodi and Liu laboratory for their helpful comments. C.B. is supported by the Swedish Research Council (Vetenskapsrådet) and the Swedish Cancer Society (Cancerfonden). C.B. is a Ragnar Söderberg Fellow in Medicine and Cancerfonden Young Investigator. S.M. is a Cancerfonden postdoctoral fellow. R.J.L. is supported by the National Key Research and Development Program of China (2021YFA1100800, 2020YFA0803400) and the National Natural Science Foundation of China (31971230,32022040).
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All authors discussed the content, researched data and contributed to the writing of the article. C.B., S.M. and R.J.L. reviewed and edited the original draft.
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C.B. and S.M. are founders and members of the scientific advisory board of SACRA Therapeutics. The other authors declare no competing interests.
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Glossary
- Acceptor stem
-
A 7–9 base pair tRNA stem with a specific CCA at the 3′ end; used to accept amino acids.
- Anticodon loop
-
A structural element in tRNAs containing a 3-nucleotide sequence complementary to the corresponding codon present in the mRNA.
- Argonaute proteins
-
A family of proteins that directly bind and mediate the function of regulatory small RNAs. The eukaryotic family is divided into Argonaute proteins and PIWI proteins.
- Cajal body
-
Nuclear membraneless organelle involved in RNA metabolism and processing.
- D-arm
-
A feature in the tertiary structure of tRNAs, consisting of the D-stem and D-loop, which are named after the presence of specific dihydrouridines (D) in the D-loop.
- D-loop
-
A structural element of the D-arm in tRNA that contains dihydrouridine residues and consists of 7–11 nucleotides enclosed by a Watson and Crick base pair.
- eIF4F
-
The eukaryotic translation initiation complex, which consists of proteins that bind the 7-methylguanosine (m7G) cap structure, thereby promoting translation initiation.
- Epididymosomes
-
Membrane-bound vesicles secreted by epididymal epithelial cells; epididymosomes are vital for male fertility.
- Multi-synthetase complex
-
Also known as the aminoacyl–tRNA synthetase complex, a large complex found in higher eukaryotes, composed of multiple aminoacyl–tRNA synthetases and scaffold proteins.
- PIWI-interacting RNAs
-
PIWI-interacting RNAs are a class of non-coding small RNAs in animals, typically 21–31 nucleotides long, which interact with PIWI proteins to regulate germline differentiation and development.
- Ribotoxins
-
Protein toxins that specifically target RNA; one of the largest categories of protein toxins found in bacteria.
- TΨC loop
-
The hairpin loop nearest the 3′ end of tRNA molecules, containing thymidine (T) and pseudouridine (Ψ) bases.
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Muthukumar, S., Li, CT., Liu, RJ. et al. Roles and regulation of tRNA-derived small RNAs in animals. Nat Rev Mol Cell Biol 25, 359–378 (2024). https://doi.org/10.1038/s41580-023-00690-z
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DOI: https://doi.org/10.1038/s41580-023-00690-z
