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RNA-modifying proteins as anticancer drug targets

Abstract

All major biological macromolecules (DNA, RNA, proteins and lipids) undergo enzyme-catalysed covalent modifications that impact their structure, function and stability. A variety of covalent modifications of RNA have been identified and demonstrated to affect RNA stability and translation to proteins; these mechanisms of translational control have been termed epitranscriptomics. Emerging data suggest that some epitranscriptomic mechanisms are altered in human cancers as well as other human diseases. In this Review, we examine the current understanding of RNA modifications with a focus on mRNA methylation, highlight their possible roles in specific cancer indications and discuss the emerging potential of RNA-modifying proteins as therapeutic targets.

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Figure 1: Some examples of RNA nucleoside modifications found in Eukaryota.
Figure 2: Location and types of predominant RNA modification in mRNA and tRNA.
Figure 3: Selected structures of human RNA methyltransferases.
Figure 4: Overlays of ALKBH demethylases and RNA reader domains.

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Acknowledgements

The authors thank N. Heifner for critical help in the development of the manuscript for this article and L. Lasky, B. Hodous and C. T. Walsh for helpful discussions. Some of the initial artwork for this article was provided by F. Forney (www.frankforney.com).

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The authors are all employees and stockholders of Accent Therapeutics.

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Protein Data Bank

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Supplementary information

Supplementary information S1 (figure)

Enzymatic reaction mechanisms of select RNA modifying proteins. (PDF 1208 kb)

Glossary

Chromatin-modifying proteins

(CMPs). A collection of DNA and histone modification writers, erasers and reader proteins that collectively control chromatin modification states and thereby provide the biochemical basis for epigenetic control of DNA transcription.

Epitranscriptomics

Refers to a collection of RNA modification mechanisms that control RNA structure, stability and function, including translation to proteins.

RNA-modifying proteins

(RMPs). A collection of RNA modification writers, erasers and reader proteins that collectively control RNA modification states and thereby provide the biochemical basis for epitranscriptomic control of RNA translation to proteins and other aspects of RNA biology.

NANOG

Gene encoding a DNA homeobox transcription factor involved in embryonic stem cell proliferation, renewal and pluripotency.

Pseudouridine synthase

(PUS). A family of enzymes that catalyse the conversion of uridine to pseudouridine in RNAs.

ADAR

RNA-specific adenosine deaminase. A family of enzymes that catalyse the conversion of adenosine to inosine in RNA.

S-adenosyl-L-methionine

(SAM). The universal methyl-donor substrate of methyltransferase catalysis.

SN2

Bimolecular nucleophilic substitution. A concerted reaction mechanism in which bond cleavage on one reactant occurs simultaneously with bond formation between that reactant and a second reacting molecule.

Transfer RNA methyltransferase

(TRM). A family of enzymes that catalyse the methylation of nucleosides in tRNA.

α-Ketoglutarate

(α-KG). A critical substrate for all enzymes of the Fe2+—α-KG-dependent dioxygenase superfamily.

TET

Ten-eleven translocation protein family. Enzymes within this family catalyse the demethylation of methylcytosine within CpG islands of chromosomal DNA.

RNA demethylases

A collection of enzymes of the ALKB family of dioxygenases that catalyse the demethylation of methylated nucleosides in various forms of RNA.

ALKB

α-Ketoglutarate-dependent dioxygenase. A family of enzymes that catalyse demethylation of methyl-nucleosides in RNA.

Fat mass and obesity-associated protein

(FTO). A member of the ALKB family of RNA demethylases.

YTH

Protein domain family, the members of which function as N6-methyladenosine reader proteins.

m6A-seq

N6-methyladenosine immunoprecipitation sequencing. A method of analysing the m6A content of RNA.

MeRIP-seq

Methylated RNA immunoprecipitation sequencing. A method of analysing the m6A content of RNA.

SCARLET

Site-specific cleavage and radioactive-labelling followed by ligation-assisted extraction and thin-layer chromatography. A method of analysing the m6A content of RNA.

m6A-LAIC-seq

N6-methyladenosine level and isoform-characterization sequencing. A method of analysing the m6A content of RNA.

Methyltransferase-like (METTL) gene family

Encodes enzymes that catalyse nucleoside methylation in RNAs.

RNA methyltransferases

(RNMTs). A family of enzymes that methylate nucleosides within various forms of RNA.

NOL1/NOP2/Sun domain family

(NSUN). A family of enzymes that catalyse methylation of nucleosides in RNAs.

DNA methyltransferases

(DNMTs). A family of enzymes that methylate cytosine within CpG islands of chromosomal DNA.

Protein arginine methyltransferase

(PRMT). A family of enzymes that catalyse methylation of arginine residues in histones and other proteins.

SAH

S-adenosyl-L-homocysteine. The universal product of SAM-dependent methyltransferase catalysis.

Protein lysine methyltransferases

(PKMTs). A family of enzymes that catalyse methylation of lysine residues in histones and other proteins.

Polycomb repressive complex 2

(PRC2). A multiprotein complex that catalyses the methylation of histone 3, lysine 27 (H3K27) using either EZH2 or EZH1 as the catalytic subunit.

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Boriack-Sjodin, P., Ribich, S. & Copeland, R. RNA-modifying proteins as anticancer drug targets. Nat Rev Drug Discov 17, 435–453 (2018). https://doi.org/10.1038/nrd.2018.71

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