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The emerging complexity of the tRNA world: mammalian tRNAs beyond protein synthesis

Nature Reviews Molecular Cell Biology volume 19, pages 45–58 (2018)Cite this article

Subjects

Key Points

  • There is an incalculable number of potential molecular tRNA species, represented by their post-transcriptionally modified forms, by the presence of isoacceptors and isodecoders as well as by the generation of tRNA fragments and the formation of complexes between tRNAs and various proteins.

  • These molecular species are active, both within and outside of translation, as regulators of cellular homeostasis.

  • Modifications of bases are prominent in regulating translation for adaptation to the local environment.

  • Fragmentation repurposes tRNAs to functions outside of translation, including regulation of gene expression and epigenetics.

  • These repurposed functions of tRNAs and their fragments may have arisen early, during the development of the genetic code.

  • The complexity of the tRNA world is so vast that the analysis of how all these functions and molecular species act together will require tools analogous to those used in designing artificial intelligence systems.

Abstract

The discovery of the genetic code and tRNAs as decoders of the code transformed life science. However, after establishing the role of tRNAs in protein synthesis, the field moved to other parts of the RNA world. Now, tRNA research is blooming again, with demonstration of the involvement of tRNAs in various other pathways beyond translation and in adapting translation to environmental cues. These roles are linked to the presence of tRNA sequence variants known as isoacceptors and isodecoders, various tRNA base modifications, the versatility of protein binding partners and tRNA fragmentation events, all of which collectively create an incalculable complexity. This complexity provides a vast repertoire of tRNA species that can serve various functions in cellular homeostasis and in adaptation of cellular functions to changing environments, and it likely arose from the fundamental role of RNAs in early evolution.

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Figure 1: The overall structure of tRNAs and the various isoacceptors and isodecoders.
Figure 2: The build-up of complexity in the tRNA world.
Figure 3: Complexes of tRNAs with binding partners.
Figure 4: Examples of the many regulatory roles of tRNAs.
Figure 5: tRNA fragments in the regulation of cell biology.
Figure 6: Emergence of tRNA structure from its individual domains.

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Acknowledgements

I thank Dr Bernhard Kuhle and Mr Ryan Shapiro for extensive efforts on the artwork, and Professor Xianglei Yang for advice on construction of thematic elements. I am most appreciative of the instructive comments made by an anonymous reviewer on the section on complexity in the Concluding Remarks. Lastly, I also thank the following colleagues in the field, who collectively made extensive comments on a draft of this manuscript: Susan Ackerman (U. California, San Diego), Paul Agris (SUNY at Albany), Qi Chen (U. Nevada School of Medicine, Reno), Peter Dedon (MIT), Michaela Fry (University of Cambridge), Michael Ibba (Ohio State University, Columbus), Pavel Ivanov (Harvard Medical School), Karin Musier-Forsyth (Ohio State University, Columbus), Tao Pan (University of Chicago), Lluis Ribas de Pouplana (Institute for Research in Biomedicine, Barcelona) and Sohail Tavazoie (Rockefeller University). This work was supported by a fellowship from the National Foundation for Cancer Research.

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  1. The Scripps Florida Research Institute, 130 Scripps Way, Jupiter, 33458, Florida, USA

    Paul Schimmel

  2. The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, 92037, California, USA

    Paul Schimmel

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Supplementary information

Supplementary information S1 (box)

Angiogenin and other nucleases involved in tRNA fragmentation (PDF 138 kb)

Supplementary information S2 (box)

Mutations in tRNA modification enzymes are associated with human diseases. (PDF 128 kb)

PowerPoint slides

Glossary

Trans-acting editing factors

Editing domains that are not linked to tRNA synthetases, where they act in cis as part of the synthetase, but rather are 'free-standing' and can erase mistakes of aminoacylation by directly binding to a mischarged tRNA.

mTOR signalling

A major signalling pathway for integrated cellular signalling pathways in eukaryotes.

Stress granules

Tightly packed aggregates of proteins and RNA that appear under stress.

RNA exosome

A multi-protein complex that degrades specific RNAs in an extracellular vesicle known as an exosome.

Integrated stress response

A response to stress found in eukaryotes, where global protein synthesis is diminished to conserve cellular energy.

Granulomas

Masses of immune cells (macrophages) that surround and sequester invading pathogens.

Dos regulon

A group of genes that act together to enable the survival and persistence of Mycobacterium tuberculosis in host cells.

Cold shock domain

A protein domain designed to bind DNA and found to facilitate survival of bacteria when exposed to drops in temperature. The domain is widely distributed in proteins throughout evolution.

G-quadruplex

A naturally occurring four-stranded nucleic acid helical structure that has a high proportion of guanine bases.

Cytochrome c

A small haem-containing mitochondrial protein that is essential for electron transport.

Apoptosome

An oligomeric protein complex minimally comprising cytochrome c and apoptosis protease-activating factor 1 (APAF1), which cleaves a protease precursor (pro-caspase 9) that then triggers downstream protein cleavage events leading to cell death.

Hormone-sensitive cancers

Cancers that grow when stimulated by specific hormones, such as oestrogen or testosterone.

Epididymis

A narrow, tightly coiled tube several metres in length that serves as the site of sperm maturation.

Retrotransposon

DNA genetic element that copies itself by reverse transcription through an RNA intermediate and can insert itself at various target sites within the genome. These elements are widespread in the human genome.

Microcephaly

A size of head that is at least two standard deviations below that of a normal head.

RNA world hypothesis

The hypothesis that RNA appeared before proteins and had many of the catalytic and ligand-binding characters of the modern proteins that eventually took over many of these functions.

Mauriceville plasmid

A circular DNA that replicates in some strains of Neurospora crassa through an RNA intermediate that has a tRNA-like structure at its 3′-end.

Telomerase

A ribonucleoprotein that catalyses the addition of nucleotide-repeat elements to the ends of chromosomes.

Ischaemia

A shortage of blood supply that deprives tissues of the oxygen and glucose needed for cell survival.

Extracellular vesicles

Membranous vesicles released from cells and containing proteins, RNAs and other cellular constituents.

Artificial intelligence systems

Computer programmes that are designed to make choices and decisions, and solve problems, by cognitive human-like, experience-based learning.

Neutral drift

The hypothesis that, at the molecular level, non-harmful (neutral) mutations are the main anomalies accounting for gene sequence variations among and between species in evolution.

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Schimmel, P. The emerging complexity of the tRNA world: mammalian tRNAs beyond protein synthesis. Nat Rev Mol Cell Biol 19, 45–58 (2018). https://doi.org/10.1038/nrm.2017.77

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