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

  • Samuel HongEmail author
  • Xiaodong Cheng
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 945)


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, 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.


Epigenetic Signal Base Excision Repair Pathway Active Site Pocket Target Base Target Recognition Domain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.







Glucosylated 5-hydroxymethylcytosine










E. coli alkylated DNA repair protein


Alkylated DNA repair protein AlkB homolog 5 in human


Chromomethylase 2 (plant specific)


Chromomethylase 3 (plant specific)


Demeter (plant)


Demeter-like protein 3 (plant)


Mammalian DNA methyltransferase 1


Mammalian DNA methyltransferase 3A


Mammalian DNA methyltransferase 3-like


Domain rearranged methyltransferase 2 (plant)


Fat mass and obesity-associated protein




J-binding protein


Methyl-CpG-binding domain


Modified cytosine restriction B


DNA methyltransferase 1 (plant)










Repressor of silencing 1 (plant specific)


SET and RING associated


Thymine DNA glycosylase


Ten-eleven translocation


Target recognition domain


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


Winged helix





The work in the authors’ laboratory is supported by grant from National Institutes of Health (GM049245-22). X.C. is a Georgia Research Alliance Eminent Scholar.


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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Department of BiochemistryEmory University School of MedicineAtlantaUSA
  2. 2.Molecular and Systems Pharmacology Graduate ProgramEmory University School of MedicineAtlantaUSA

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