Abstract
Chemically modified bases exist naturally in genomic DNA. Research into these bases has been invigorated by the discovery of several modified bases in the mammalian genome, in particular 5-methylcytosine and its oxidized derivatives, such as 5-(hydroxymethyl)cytosine and 5-formylcytosine, as well as the enzymes that form and process them, such as the DNA methyltransferases and the ten-eleven translocation enzymes. In this Review, we provide an overview of natural modified bases that have been reported in DNA, our current knowledge of their roles, and the techniques that have enabled us to probe their functions. Analytical methods have been invaluable in helping to advance this field. For example, chemical and enzymatic methods have provided the means to detect and decode modified bases, giving rise to an expanding array of sequencing approaches. Advanced liquid chromatography and tandem mass spectrometry have provided the means to detect and quantify modified bases with very high sensitivity, increasing the prospect of discovering unknown modifications. It is already evident that natural modified DNA bases and their associated enzymology are of fundamental importance to normal biology and to disease. The next decade promises to yield more insights, discoveries and applications from this burgeoning field of research.
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Acknowledgements
The Balasubramanian laboratory is supported by core funding from Cancer Research UK (C14303/A17197). S.B. is a senior investigator of the Wellcome Trust (Grant No. 099232/z/12/z).
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Glossary
- Transcription factors
-
Proteins that bind to a specific DNA sequence to control the transcription of the genetic information from DNA to RNA.
- Restriction methylation
-
DNA methylation that protects bacteria from restriction endonuclease enzymes, providing a defence mechanism against invasion by bacteriophages and viruses.
- Promoters
-
Regions of DNA that are located near to transcription start sites and control transcription initiation.
- Retrotransposons
-
Genetic elements that are transcribed into RNA, then reverse-transcribed back into DNA and inserted into the genome.
- Genomic imprinting
-
An epigenetic marking of one copy of the gene (from the mother or father) that ensures gene expression in a parent-of-origin-specific manner.
- Transposon silencing
-
Gene silencing of transposons by epigenetic mechanisms, including DNA methylation and the effect of small non-coding RNAs, which prevents transcription and ensures genome stability.
- Histone modifications
-
Post-translational chemical modifications of amino acid residues on a histone.
- Chromatin-remodelling proteins
-
Proteins that control access to the genetic information by either inducing histone modifications or using energy to alter histone–DNA interactions.
- CpG islands
-
(CGIs). Regions with high cytosine-phosphate-guanine (CpG) dinucleotide density.
- Pluripotent stem cells
-
Cells that can differentiate into any other tissue of the body.
- Enhancer regions
-
Regulatory regions of the genome that are marked by histone modifications and enhance the transcription of their associated genes when bound to transcription factors.
- Base excision repair
-
(BER). A cellular mechanism that removes small base lesions, caused by mismatched or modified DNA bases, from the DNA.
- Histone octamer
-
An eight-protein complex of two histone H2A–H2B dimers and two histone H3–H4 dimers that together form the core of the nucleosome.
- B cells
-
A type of white blood cell that is fundamental to the adaptive immune system.
- Class-switch recombination
-
A process whereby B cells rearrange parts of the immunoglobulin heavy chain locus to generate antibodies with different properties.
- Telomeric regions
-
Repetitive nucleotide sequences that protect the ends of chromosomes.
- Repetitive elements
-
Sequences that occur multiple times throughout the genome.
- RNA polymerase II
-
An enzyme that catalyses the transcription of DNA to RNA.
- Transfer RNA
-
An adaptor RNA and amino acid carrier that helps to decode mRNA for translation into the synthesis of proteins.
- Restriction endonucleases
-
Enzymes that cut DNA at endogenous phosphodiester bonds.
- β-Elimination
-
DNA cleavage at the phosphodiester bond resulting in the elimination of the 3′-phosphate residue.
- δ-Elimination
-
DNA cleavage at the phosphodiester bond resulting in the elimination of the 5′-phosphate residue.
- Clustered regularly interspaced short palindromic repeats (CRISPR) systems
-
Genome-editing systems, such as CRISPR–Cas9, that rely on a bacterial virus-defence mechanism involving repetitive DNA sequences that contain snippets of viral DNA. By manipulating CRISPR systems, DNA can be cut at a desired location, allowing genes to be removed or added.
- Transcription activator-like effectors
-
(TALEs). Proteins that can be programmed to target specific DNA sequences in the genome.
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Raiber, EA., Hardisty, R., van Delft, P. et al. Mapping and elucidating the function of modified bases in DNA. Nat Rev Chem 1, 0069 (2017). https://doi.org/10.1038/s41570-017-0069
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DOI: https://doi.org/10.1038/s41570-017-0069
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