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Role of RNA modifications in cancer

Abstract

Specific chemical modifications of biological molecules are an efficient way of regulating molecular function, and a plethora of downstream signalling pathways are influenced by the modification of DNA and proteins. Many of the enzymes responsible for regulating protein and DNA modifications are targets of current cancer therapies. RNA epitranscriptomics, the study of RNA modifications, is the new frontier of this arena. Despite being known since the 1970s, eukaryotic RNA modifications were mostly identified on transfer RNA and ribosomal RNA until the last decade, when they have been identified and characterized on mRNA and various non-coding RNAs. Increasing evidence suggests that RNA modification pathways are also misregulated in human cancers and may be ideal targets of cancer therapy. In this Review we highlight the RNA epitranscriptomic pathways implicated in cancer, describing their biological functions and their connections to the disease.

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Fig. 1: Internal RNA modifications.
Fig. 2: Distribution of the seven post-transcriptional modifications on different RNA subtypes.
Fig. 3: The N6-methyladenosine machinery and its roles in cancer.
Fig. 4: The main functions of RNA-modifying enzymes in cancer beyond those of the N6-methyladenosine modification.
Fig. 5: 5′ cap structures present on different RNA subtypes.
Fig. 6: RNA modification writers, readers and erasers can have either promoting or inhibitory effects on the hallmarks of cancer.

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Acknowledgements

The authors apologize to colleagues whose work was not acknowledged owing to space limitations. The authors thank A. Bannister for critically reading the manuscript and for the insightful discussions. Work in the Kouzarides laboratory is supported by grants from Cancer Research UK (grant reference RG17001) and the European Research Council (project number 268569), in addition to benefiting from core support from the Wellcome Trust (Core Grant reference 092096) and Cancer Research UK (grant reference C6946/A14492). I.B. is funded by a Kay Kendall Leukaemia Fund project grant (grant reference RG88664) and Cancer Research UK (grant reference RG86786).

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I.B. researched data for the article. T.K. contributed substantially to discussion of the content. I.B. and T.K contributed equally to writing the article and to reviewing and editing the manuscript.

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Correspondence to Tony Kouzarides.

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T.K. is a co-founder of Abcam and Storm Therapeutics, Cambridge, UK. I.B. declares no competing interests.

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Glossary

Watson–Crick edge

The side of purine and pyrimidine bases involved in the canonical Watson–Crick base pairing.

Cap

A characteristic structure of all eukaryotic mRNAs that consists of a N7-methylated guanine nucleotide bound to the first nucleotide of the mRNA via a 5′–5′ triphosphate bond.

Primary miRNA

(pri-miRNA). Primary transcript from which one or several microRNAs originate. In many cases the same pri-miRNA can be a primary transcript for mRNA and other non-coding RNAs.

Small nuclear RNA

(snRNA). A class of small non-coding RNA localized in the nucleus of eukaryotic cells as part of ribonucleoprotein complexes mediating mRNA maturation and splicing. They are functionally different from small nucleolar RNAs, which are involved in ribosome biogenesis.

Hypomorphic mutations

Mutations partially impairing the function of the encoded protein.

Enhancer RNA

(eRNA). Short (50–200 nucleotides) non-coding RNAs transcribed from enhancer regions and involved in transcriptional regulation both in cis (adjacent loci) and in trans (distant loci).

Bisulfite sequencing

Technique making possible the mapping of 5-methylcytosine (m5C)-modified nucleotides within DNA or RNA. Cytosine nucleotides are converted into uracil on treatment with bisulfite, while methylated nucleotides are protected from this conversion. Methylation sites can then be detected by standard sequencing methods.

Vault RNA

Vaults, large ribonucleoprotein particles in the cytoplasm isolated from higher eukaryotes, contain a small portion of small untranslated RNAs called vault RNAs. Vault RNA is transcribed by RNA polymerase II and, despite being part of the vault complex, does not have a structural role.

Hoogsteen base pairing

A variation of base pairing in nucleic acids, formed by the interaction of the N7 position (as a hydrogen bond acceptor) and C6 amino group (as a donor) of a purine base, with the Watson–Crick (N3–C4) surface of a pyrimidine base.

G-quadruplex structures

Formed in DNA and RNA molecules rich in guanines where four guanine bases can associate by Hoogsteen pairings to form a guanine tetrad, which in turn can stack on top of each other.

Exonucleases

Enzymes removing single nucleotides from the ends of a DNA or RNA polynucleotide chain.

Small nucleolar RNA

(snoRNA). A non-coding RNA localized in the nucleolus and part of ribonucleoprotein complexes involved in the modification of ribosomal RNA precursors and transfer RNAs.

Precursor miRNA

(pre-miRNA). Hairpin intermediate precursors of microRNAs (miRNAs) produced by the cleavage of primary miRNAs by Drosha ribonuclease III (DROSHA) and microprocessor complex subunit DGCR8.

Exoribonuclease

Enzyme that removes single nucleotides from the ends of an RNA polynucleotide chain.

Wilms tumours

Rare kidney cancers affecting children.

Transposable elements

Genomic elements capable of changing their position and copy numbers within the genome. DNA transposons do not go through an RNA intermediate, while retrotransposons are transcribed into an RNA intermediate and successively retrotranscribed to double-stranded DNA.

Alu repeats

A type of genomic short interspersed element (SINE) representing the most common transposable element in the human genome with more than one million copies. They can influence gene expression and are involved in disease, including cancer.

Seed sequence

Conserved heptameric region of a microRNA, typically positioned at the 5′ end determining target specificity (the binding of the microRNA to its target mRNA).

Wobble position

The third base of a codon (or anticodon) characterized by promiscuous pairings. Modifications of this position on transfer RNAs allow non-Watson–Crick base pairing to occur and allow different codons to encode the same amino acid.

Elongator complex

Multisubunit protein complex associated with RNA polymerase II and involved in 5-methoxycarbonylmethyl (mcm5) and 5-carbamoylmethyl (ncm5) modifications on uridines at wobble positions in transfer RNA and histone acetylation.

Internal ribosome entry site

(IRES). RNA elements that allow internal cap-independent translation initiation. They are common in viral RNAs but are also found in stress-induced transcripts in eukaryotic cells.

Rossmann fold

Structural motif commonly found in proteins that bind to nucleotides.

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Barbieri, I., Kouzarides, T. Role of RNA modifications in cancer. Nat Rev Cancer 20, 303–322 (2020). https://doi.org/10.1038/s41568-020-0253-2

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