Abstract
DNA methylation is a hot topic in basic and biomedical research. Despite tremendous progress in understanding the structures and biochemical properties of the mammalian DNA methyltransferases (DNMTs), principles of their targeting and 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 containing a catalytic C-terminal domain and a complex N-terminal part with diverse targeting and regulatory functions. The sub-nuclear localization of DNMTs plays an important role in their biological function: DNMT1 is localized to replicating DNA and heterochromatin via interactions with PCNA and UHRF1 and direct binding to the heterochromatic histone modifications H3K9me3 and H4K20me3. DNMT3 enzymes bind to heterochromatin via protein multimerization and are targeted to chromatin by their ADD, PWWP, and UDR domains, binding to unmodified H3K4, H3K36me2/3, and H2AK119ub1, respectively. In recent years, a novel regulatory principle has been discovered in DNMTs, as structural and functional data demonstrated that the catalytic activities of DNMT enzymes are under a tight allosteric control by their different N-terminal domains with autoinhibitory functions. This mechanism provides numerous possibilities for the precise regulation of the methyltransferases via controlling the binding and release of the autoinhibitory domains by protein partners, chromatin interactions, non-coding RNAs, or posttranslational modifications of the DNMTs. In this chapter, we summarize key enzymatic properties of DNMTs, viz. their specificity and processivity, and afterwards focus on the regulation of their activity and targeting via allosteric processes, protein interactions, and posttranslational modifications.
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Abbreviations
- 5mC:
-
5-methylcytosine
- ADD domain:
-
ATRX-Dnmt3-DNMT3L domain
- AdoHcy:
-
S-adenosyl-L-homocysteine
- AdoMet:
-
S-adenosyl-L-methionine
- AML:
-
acute myeloid leukaemia
- BAH domain:
-
Bromo-adjacent homology domain
- CpG:
-
cytosine-guanine dinucleotide sequence
- DMAP1:
-
DNA methyltransferase-associated protein 1
- DMR:
-
differentially methylated region
- DNMT:
-
(mammalian) DNA nucleotide methyltransferase
- ES cells:
-
embryonic stem cells
- HDAC:
-
histone deacetylase
- ICF:
-
Immunodeficiency-centromeric instability-facial anomalies syndrome
- lncRNA:
-
long non-coding RNA
- KG repeats:
-
lysine-glycine repeats
- KO:
-
knock out
- MBD:
-
methyl-binding domain
- miRNA:
-
micro-RNA
- MTase:
-
methyltransferase
- ncRNA:
-
non-coding RNA
- PCNA:
-
proliferating cell nuclear antigen
- PBD:
-
PCNA binding domain
- PHD:
-
plant homeodomain
- PTM:
-
posttranslational modification
- RING:
-
really interesting new gene
- RFTD:
-
replication foci targeting domain
- SIRT1:
-
sirtuin 1
- SRA domain:
-
SET and RING-associated domain
- TET:
-
Ten-eleven translocation
- TRD:
-
target recognition domain
- TTD:
-
tandem Tudor domain
- UBL:
-
ubiquitin-like domain
- UDR:
-
ubiquitin-dependent recruitment
- UHRF1:
-
ubiquitin-like with PHD and ring finger domains 1
- USP7:
-
ubiquitin-specific peptidase 7
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Jurkowska, R.Z., Jeltsch, A. (2022). Enzymology of Mammalian DNA Methyltransferases. 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_4
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