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Recent Advances on DNA Base Flipping: A General Mechanism for Writing, Reading, and Erasing DNA Modifications

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DNA Methyltransferases - Role and Function

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1389))

Abstract

The modification of DNA bases is a classic hallmark of epigenetics. Four forms of modified cytosine—5-methylcytosine, 5-hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine—have been discovered in eukaryotic DNA. In addition to cytosine carbon-5 modifications, cytosine and adenine methylated in the exocyclic amine—N4-methylcytosine and N6-methyladenine—are other modified DNA bases discovered even earlier. Each modified base can be considered a distinct epigenetic signal with broader biological implications beyond simple chemical changes. Since 1994, several crystal structures of proteins and enzymes involved in writing, reading, and erasing modified bases have become available. Here, we present a structural synopsis of writers, readers, and erasers of the modified bases from prokaryotes and eukaryotes. Despite significant differences in structures and functions, they are remarkably similar regarding their engagement in flipping a target base/nucleotide within DNA for specific recognitions and/or reactions. We thus highlight base flipping as a common structural framework broadly applied by distinct classes of proteins and enzymes across phyla for epigenetic regulations of DNA.

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Abbreviations

5caC:

5-carboxylcytosine

5fC:

5-formylcytosine

5ghmC:

Glucosylated 5-hydroxymethylcytosine

5hmC:

5-hydroxymethylcytosine

5mC:

5-methylcytosine

αKG:

α-ketoglutarate

AdoHcy:

S-adenosyl-l-homocysteine (SAH)

AdoMet:

S-adenosyl-l-methionine (SAM)

AlkB:

E. coli Alkylated DNA repair protein AlkB

ALKBH5:

Alkylated DNA repair protein AlkB homolog 5 in human

CMT2:

Chromomethylase 2 (plant specific)

CMT3:

Chromomethylase 3 (plant specific)

DME:

Demeter (plant)

DML3:

Demeter-like protein 3 (plant)

DNMT1:

Mammalian DNA methyltransferase 1

DNMT3A:

Mammalian DNA methyltransferase 3A

DNMT3L:

Mammalian DNA methyltransferase 3-like

DRM2:

Domain rearranged methyltransferase 2 (plant)

FTO:

Fat mass and obesity-associated protein

HhH:

Helix-hairpin-helix

JBP:

J-binding protein

MBD:

Methyl-CpG binding domain

McrB:

Modified cytosine restriction B

Met1:

DNA methyltransferase 1 (plant)

MTase:

Methyltransferase

N4mC:

N4-methylcytosine

N6mA:

N6-methyladenine

NOG:

N-oxalylglycine

ROS1:

Repressor of silencing 1 (plant specific)

SRA:

SET- and RING-associated

TDG:

Thymine DNA glycosylase

TET:

Ten-eleven translocation

TRD:

Target recognition domain

Uhrf1:

Ubiquitin-like-containing PHD and RING finger domains protein 1

WH:

Winged helix

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Acknowledgments

We thank members of the Cheng laboratory during the last three decades of research on DNA base flipping. The work in the authors’ laboratory is currently supported by grant from the National Institutes of Health (R35GM134744) and the Cancer Prevention and Research Institute of Texas (CPRIT RR160029). X.C. is a CPRIT Scholar in Cancer Research.

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  1. Ren Ren and John R. Horton contributed equally with all other contributors.

Authors and Affiliations

  1. Department of Epigenetics and Molecular Carcinogenesis, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Ren Ren, John R. Horton & Xiaodong Cheng

  2. McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA

    Samuel Hong

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  1. Ren Ren
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  2. John R. Horton
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  3. Samuel Hong
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  4. Xiaodong Cheng
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Correspondence to Xiaodong Cheng .

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  1. Department of Biochemistry, Institute of Biochemistry and Technical Biochemistry, University of Stuttgart, Stuttgart, Germany

    Albert Jeltsch

  2. School of Biosciences, Division of Biomedicine, Cardiff University, Cardiff, UK

    Renata Z. Jurkowska

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Ren, R., Horton, J.R., Hong, S., Cheng, X. (2022). Recent Advances on DNA Base Flipping: A General Mechanism for Writing, Reading, and Erasing DNA Modifications. In: Jeltsch, A., Jurkowska, R.Z. (eds) DNA Methyltransferases - Role and Function. Advances in Experimental Medicine and Biology, vol 1389. Springer, Cham. https://doi.org/10.1007/978-3-031-11454-0_12

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