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Enzymology of Mammalian DNA Methyltransferases

  • Renata Z. JurkowskaEmail author
  • Albert JeltschEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 945)

Abstract

DNA methylation is currently one of the hottest topics in basic and biomedical research. Despite tremendous progress in understanding the structures and biochemical properties of the mammalian DNA nucleotide methyltransferases (DNMTs), principles of their regulation in cells have only begun to be uncovered. In mammals, DNA methylation is introduced by the DNMT1, DNMT3A, and DNMT3B enzymes, which are all large multi-domain proteins. These enzymes contain a catalytic C-terminal domain with a characteristic cytosine-C5 methyltransferase fold and an N-terminal part with different domains that interacts with other proteins and chromatin and is involved in targeting and regulation of the DNMTs. The subnuclear localization of the DNMT enzymes plays an important role in their biological function: DNMT1 is localized to replicating DNA via interaction with PCNA and UHRF1. DNMT3 enzymes bind to heterochromatin via protein multimerization and are targeted to chromatin by their ADD and PWWP domains. Recently, a novel regulatory mechanism has been discovered in DNMTs, as latest structural and functional data demonstrated that the catalytic activities of all three enzymes are under tight allosteric control of their N-terminal domains having autoinhibitory functions. This mechanism provides numerous possibilities for the precise regulation of the methyltransferases via controlling the binding and release of autoinhibitory domains by protein factors, noncoding RNAs, or by posttranslational modifications of the DNMTs. In this chapter, we summarize key enzymatic properties of DNMTs, including their specificity and processivity, and afterward we focus on the regulation of their activity and targeting via allosteric processes, protein interactors, and posttranslational modifications.

Keywords

PWWP Domain Subnuclear Localization DNMT3 Protein DNMT3 Enzyme CXXC 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.

Abbreviations

ADD domain

ATRX-DNMT3-DNMT3L domain

AdoHcy

S-Adenosyl-L-homocysteine

AdoMet

S-Adenosyl-L-methionine

BAH

Bromo-adjacent homology domain

CpG

Cytosine-guanine dinucleotide separated by a phosphate

DMAP1

DNA methyltransferase-associated protein 1

DMR

Differentially methylated region

DNMT

(Mammalian) DNA nucleotide methyltransferase

HDAC

Histone deacetylase

KG repeats

Lysine-glycine repeats

KO

Knockout

MBD

Methyl-binding domain

miRNA

MicroRNA

MTase

Methyltransferase

5mC

5-Methylcytosine

ncRNA

Non(protein)-coding RNA

PCNA

Proliferating cell nuclear antigen

PBD

PCNA-binding domain

PHD

Plant homeodomain

PTM

Posttranslational modification

RFTD

Replication foci-targeting domain

SIRT1

Sirtuin 1

SRA domain

SET- and RING-associated domain

TRD

Target recognition domain

TTD

Tandem Tudor domain

UHRF1

Ubiquitin-like with PHD and ring finger domains 1

USP7

Ubiquitin-specific peptidase 7

ZHX1

Zinc finger and homeobox protein 1

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© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.BioMed X Innovation CenterHeidelbergGermany
  2. 2.Institute of Biochemistry, Faculty of ChemistryUniversity of StuttgartStuttgartGermany

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