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Transfer RNAs as dynamic and critical regulators of cancer progression

Nature Reviews Cancer volume 23, pages 746–761 (2023)Cite this article

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Abstract

Transfer RNAs (tRNAs) have been historically viewed as non-dynamic adaptors that decode the genetic code into proteins. Recent work has uncovered dynamic regulatory roles for these fascinating molecules. Advances in tRNA detection methods have revealed that specific tRNAs can become modulated upon DNA copy number and chromatin alterations and can also be perturbed by oncogenic signalling and transcriptional regulators in cancer cells or the tumour microenvironment. Such alterations in the levels of specific tRNAs have been shown to causally impact cancer progression, including metastasis. Moreover, sequencing methods have identified tRNA-derived small RNAs that influence various aspects of cancer progression, such as cell proliferation and invasion, and could serve as diagnostic and prognostic biomarkers or putative therapeutic targets in various cancers. Finally, there is accumulating evidence, including from genetic models, that specific tRNA synthetases — the enzymes responsible for charging tRNAs with amino acids — can either promote or suppress tumour formation. In this Review, we provide an overview of how deregulation of tRNAs influences cancer formation and progression.

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Fig. 1: Transfer RNA structure and biogenesis.
Fig. 2: Roles of mature transfer RNAs in oncogenic transformation and cancer progression.
Fig. 3: Regulation of transfer RNA expression in cancer.
Fig. 4: Examples of oncogenic and tumour-suppressive transfer RNA-derived fragments in cancer.

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Acknowledgements

The authors thank the members of the Tavazoie laboratory for critically reading the manuscript and for their helpful suggestions and comments. The authors apologize to all the scientists whose work could not be cited owing to space limitations. S.F.T. and A.M.P. were supported by grants from the National Cancer Institute of the National Institutes of Health under award numbers R01CA257153, R35CA274446 and U54CA261701, as well as the Black Family Metastasis Center and the Breast Cancer Research Foundation. Molecular graphics were performed with UCSF ChimeraX, developed by the Resource for Biocomputing, Visualization and Informatics at the University of California, San Francisco, with support from National Institutes of Health R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases.

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  1. Laboratory of Systems Cancer Biology, The Rockefeller University, New York, NY, USA

    Alexandra M. Pinzaru & Sohail F. Tavazoie

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Glossary

Argonaute 2 (AGO2) cleavage assay

An in vitro assay that uses recombinant AGO2 to show specific cleavage of target oligonucleotides.

Epistatic interactions

Interactions between two or more genes that influence a particular phenotype.

Lineage-negative haematopoietic stem and progenitor cells

Immature blood cells that lack surface protein markers found on mature blood cells.

Rare codons

Codons found with the lowest frequency in genes compared with synonymous codons in the same group.

Ribosome

An essential ribonucleoprotein complex that performs protein synthesis in cells.

Ribosome profiling

A technique that provides a snapshot of all ribosome-bound messenger RNAs in cells with codon-level resolution.

RNA polymerase III

(Pol III). An RNA polymerase complex that translates short, non-coding RNAs, including transfer RNAs, 5S ribosomal RNA, U6 small nuclear RNA, vault RNA and other small RNAs.

tRNA misacylation

The charging of a transfer RNA with the wrong amino acid, not the amino acid cognate to the anticodon of the transfer RNA.

Wobble pairing

Non-Watson–Crick base pairing of the first anticodon nucleoside: inosine can pair with adenosine, uridine or cytidine; guanosine can pair with cytidine or uridine; uridine can pair with adenosine or guanosine.

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Pinzaru, A.M., Tavazoie, S.F. Transfer RNAs as dynamic and critical regulators of cancer progression. Nat Rev Cancer 23, 746–761 (2023). https://doi.org/10.1038/s41568-023-00611-4

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