Abstract
The ability of chemical modifications of single nucleotides to alter the electrostatic charge, hydrophobic surface and base pairing of RNA molecules is exploited for the clinical use of stable artificial RNAs such as mRNA vaccines and synthetic small RNA molecules — to increase or decrease the expression of therapeutic proteins. Furthermore, naturally occurring biochemical modifications of nucleotides regulate RNA metabolism and function to modulate crucial cellular processes. Studies showing the mechanisms by which RNA modifications regulate basic cell functions in higher organisms have led to greater understanding of how aberrant RNA modification profiles can cause disease in humans. Together, these basic science discoveries have unravelled the molecular and cellular functions of RNA modifications, have provided new prospects for therapeutic manipulation and have led to a range of innovative clinical approaches.
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Acknowledgements
M.F. received funding from the Helmholtz Association (W2/W3-106), Cancer Research UK (CR-UK; C10701/A15181) and Worldwide Cancer Research (21-0223). S.D. was supported by an EMBO (European Molecular Biology Organization) long-term fellowship (LTFS48) and by the Leon Fredericq Foundation. M.H. and M.F. are part of TRR319 RMaP (439669440).
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Glossary
- Anticodon
-
A sequence of three nucleotides on a tRNA molecule that recognizes and binds to a complementary trinucleotide codon sequence on mRNA during protein synthesis.
- Antisense oligonucleotides
-
(ASOs). Short synthetic strands of nucleic acids that bind to complementary RNA sequences, offering targeted gene regulation and therapeutic potential for various genetic and disease-related applications.
- Base stacking
-
Non-covalent interaction between adjacent aromatic nitrogenous bases in RNA that contributes to the stability of the secondary and tertiary structures of the RNA.
- Charged tRNAs
-
tRNA molecules that carry a specific amino acid and are ready to participate in protein synthesis during translation.
- Codon optimality
-
Refers to the preferential use of certain synonymous codons over others in a given organism or gene owing to differences in their usage frequency or interactions with tRNA molecules and ribosomes.
- Elongator complex
-
A multi-protein complex composed of two subcomplexes, ELP1–ELP2–ELP3 and ELP4–ELP5–ELP6, that modifies tRNAs in their wobble position to regulate protein synthesis and ensure proteome stability.
- Fragile X syndrome
-
A genetic disorder characterized by developmental delays, learning disabilities and social and behavioural problems, caused by a mutation in FMR1, which is needed for brain development.
- Mitochondrial respiratory chain complex deficiency
-
A type of mitochondrial disease caused by defects in the enzymes involved in oxidative phosphorylation (OXPHOS), resulting in impaired energy production.
- Oxidative phosphorylation
-
(OXPHOS). A metabolic pathway taking place inside mitochondria, in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy in the form of ATP.
- Queuosine
-
A hypermodified guanosine present in certain tRNAs in bacteria and eukaryotes containing the nucleobase queuine, which has a role in maintaining the proper reading frame during mRNA translation.
- Unfolded protein response
-
A cellular stress response mechanism that is activated by the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum.
- Wobble position
-
The third nucleotide position of the anticodon trinucleotide sequence, which pairs with more than one complementary nucleotide in the mRNA codon.
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Delaunay, S., Helm, M. & Frye, M. RNA modifications in physiology and disease: towards clinical applications. Nat Rev Genet 25, 104–122 (2024). https://doi.org/10.1038/s41576-023-00645-2
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DOI: https://doi.org/10.1038/s41576-023-00645-2
