Comprehensive structure-function characterization of DNMT3B and DNMT3A reveals distinctive de novo DNA methylation mechanisms.
Animals
Catalytic Domain
Cell Line
CpG Islands
/ genetics
DNA (Cytosine-5-)-Methyltransferases
/ genetics
DNA Methylation
DNA Methyltransferase 3A
Embryonic Stem Cells
Enzyme Assays
Epigenesis, Genetic
Face
/ abnormalities
Humans
Mice
Mutation
Primary Immunodeficiency Diseases
/ genetics
Structure-Activity Relationship
Substrate Specificity
/ genetics
X-Ray Diffraction
DNA Methyltransferase 3B
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
03 07 2020
03 07 2020
Historique:
received:
25
09
2019
accepted:
18
02
2020
entrez:
5
7
2020
pubmed:
6
7
2020
medline:
29
8
2020
Statut:
epublish
Résumé
Mammalian DNA methylation patterns are established by two de novo DNA methyltransferases, DNMT3A and DNMT3B, which exhibit both redundant and distinctive methylation activities. However, the related molecular basis remains undetermined. Through comprehensive structural, enzymology and cellular characterization of DNMT3A and DNMT3B, we here report a multi-layered substrate-recognition mechanism underpinning their divergent genomic methylation activities. A hydrogen bond in the catalytic loop of DNMT3B causes a lower CpG specificity than DNMT3A, while the interplay of target recognition domain and homodimeric interface fine-tunes the distinct target selection between the two enzymes, with Lysine 777 of DNMT3B acting as a unique sensor of the +1 flanking base. The divergent substrate preference between DNMT3A and DNMT3B provides an explanation for site-specific epigenomic alterations seen in ICF syndrome with DNMT3B mutations. Together, this study reveals distinctive substrate-readout mechanisms of the two DNMT3 enzymes, implicative of their differential roles during development and pathogenesis.
Identifiants
pubmed: 32620778
doi: 10.1038/s41467-020-17109-4
pii: 10.1038/s41467-020-17109-4
pmc: PMC7335073
doi:
Substances chimiques
DNMT3A protein, human
0
Dnmt3a protein, mouse
0
DNA (Cytosine-5-)-Methyltransferases
EC 2.1.1.37
DNA Methyltransferase 3A
EC 2.1.1.37
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3355Subventions
Organisme : NIEHS NIH HHS
ID : R21 ES025392
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA215284
Pays : United States
Organisme : NIEHS NIH HHS
ID : R35 ES031707
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016086
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM119721
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA211336
Pays : United States
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