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Chemical Compounds Targeting DNA Methylation and Hydroxymethylation

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Chemical Epigenetics

Part of the book series: Topics in Medicinal Chemistry ((TMC,volume 33))

Abstract

DNA methylation and its oxidised forms participate in the interpretation and regulation of the human genome. Many questions arise around the enzymes responsible for these chemical modifications on DNA, and their roles in transcriptional regulation. These epigenetic marks are very dynamic and specific in their location and context (tissues, diseases, etc.). We review the major enzymes involved in DNA methylation and oxidation, with a focus on the DNA methyltransferases and TET enzymes. The principal compounds that inhibit these enzymes are presented since they will help address these questions.

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Abbreviations

1-mA:

1-Methyl-adenine

2OG:

2-Oxoglutarate

3-mC:

3-Methylcytosine

3-mT:

3-Methyl-thymine

5-aza-C:

5-Aza-cytosine

5-azadC:

5-Aza-2′-deoxycytosine

5-caC:

5-Carboxycytosine

5-fC:

5-Formylcytosine

5-hmC:

5-Hydroxymethylcytosine

5-mC:

5-Methylcytosine

5-xC:

5-Modified cytosine

6-mA:

6-Methyl-adenine

AML:

Acute myeloid leukaemia

AM-PD:

Active modification-passive dilution

BAH1 and BAH2:

Bromo-adjacent homology domains 1 and 2

BER:

Base excision repair

CFP1:

CpG-binding protein, CXXC finger protein 1

CMML:

Chronic myelomonocytic leukaemia

CpA:

Cytidine pairing adenosine

CpC:

Cytidine pairing cytidine

CpG:

Cytidine pairing guanosine

CpT:

Cytidine pairing thymidine

CXXC:

CXXC domain

DMAP domain:

DNA methyltransferase-associated protein 1-interacting domain

DNMT:

C5-DNA methyltransferase

DSBH:

Double-stranded β-ηelix

EGCG:

Epigallocatechin gallate

ELISA:

Enzyme-linked immunosorbent assay

EMA:

European Medicines Agency

FDA:

Food and Drug Administration

FH:

Fumarate hydratase

FTO:

Fat mass and obesity-associated protein

HDAC:

Histone deacetylase

IDAX:

Inhibition of the Dvl and Axin complex

IDH:

Isocitrate dehydrogenase

LCI:

Low-complexity insert

LC-MS:

Liquid chromatography-mass spectrometry

MALDI-TOF:

Matrix-assisted laser desorption/ionisation time-of-flight

MBP:

Methyl-binding protein

MDS:

Myelodysplastic syndrome

MLL:

Mixed lineage leukaemia

mTet1:

Murine TET

NgTet1:

Naegleria gruberi TET

NLS:

Nuclear localisation signal

NOG:

N-Oxalylglycine

PBD:

PCNA-binding domain

PHD:

Plant homeodomain

PRMT:

Protein arginine methyltransferase

PWWP:

Proline-tryptophan-tryptophan-proline domain

R/S-2HG:

R/S-2-hydroxyglutarate

RFTD:

Replication foci targeting sequence (RFTS) domain

ROS1:

Repressor of silencing 1

SAH/AdoHys:

S-Adenosyl-l-homocysteine

SAM/AdoMet:

S-Adenosyl-l-methionine

SDH:

Succinate dehydrogenase

SPR:

Surface plasmon resonance

TCA:

Tricarboxylic acid

TDG:

Thymidine-DNA glycosylase

TET:

Ten-eleven translocation

TLC:

Thin-layer chromatography

TRDMT1:

tRNA aspartic acid methyltransferase

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Acknowledgement

RB is supported by the Engineering and Physical Science Research Council and University of Oxford. AK gratefully acknowledges the Royal Society for the Dorothy Hodgkin Fellowship and the European Research Council Starting Grant (EPITOOLS-679479) and the Cancer Research UK Oxford Centre Development Fund (C5255/A18085). We apologise for the incomplete citations of research due to space constraints.

The authors acknowledge the EU COST Action CM1406. PBA is supported by PlanCancer2014-2019 (EPIG-2014-01).

Compliance with Ethical Standards

Funding: RB is supported by the Engineering and Physical Science Research Council and University of Oxford. AK gratefully acknowledges the Royal Society for the Dorothy Hodgkin Fellowship and the European Research Council Starting Grant (EPITOOLS-679479) and the Cancer Research UK Oxford Centre. We apologise for the incomplete citations of research due to space constraints.

The authors acknowledge the EU COST Action CM1406. PBA is supported by PlanCancer 2014–2019 (EPIG-2014-01). PBA was recipient of the French Oversea Fellowship of the French Government and Churchill College Cambridge UK.

Conflict of Interest:

Roman Belle declares that he has no conflict of interest. Akane Kawamura declares that she has no conflict of interest and Paola B. Arimondo declares that she has no conflict of interest.

Ethical Approval:

This chapter does not contain any studies with human participants or animals performed by any of the authors.

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Authors and Affiliations

  1. Department of Chemistry, University of Oxford, Chemistry Research Laboratory, Oxford, UK

    Roman Belle & Akane Kawamura

  2. Radcliffe Department of Medicine, University of Oxford, Wellcome Centre for Human Genetics, Oxford, UK

    Akane Kawamura

  3. Epigenetic Chemical Biology, Institut Pasteur, CNRS UMR3523, Paris, France

    Paola B. Arimondo

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Correspondence to Akane Kawamura or Paola B. Arimondo .

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  1. Sapienza University of Rome, Rome, Italy

    Antonello Mai

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Belle, R., Kawamura, A., Arimondo, P.B. (2019). Chemical Compounds Targeting DNA Methylation and Hydroxymethylation. In: Mai, A. (eds) Chemical Epigenetics. Topics in Medicinal Chemistry, vol 33. Springer, Cham. https://doi.org/10.1007/7355_2019_76

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