Mechanism studies of the activation of DNA methyltransferase DNMT1 triggered by histone H3 ubiquitination, revealed by multi-scale molecular dynamics simulations

DNMT1 is a DNA methyltransferase that catalyzes and maintains methylation in CpG dinucleotides. It blocks the entrance of DNA into the catalytic pocket via the replication foci targeting sequence (RFTS) domain. Recent studies have shown that an H3-tail-conjugated two-mono-ubiquitin mark (H3Ub2) acti...

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Bibliographic Details
Published in:Science China. Life sciences 2023-02, Vol.66 (2), p.313-323
Main Authors: Sun, Jixue, Liu, Fei, Yuan, Longxiao, Pang, Ning-Ning, Zhu, Bing, Yang, Na
Format: Article
Language:English
Subjects:
Biomedical and Life Sciences
Conformation
CpG islands
DNA (Cytosine-5-)-Methyltransferases - chemistry
DNA (Cytosine-5-)-Methyltransferases - genetics
DNA (Cytosine-5-)-Methyltransferases - metabolism
DNA - metabolism
DNA Methylation
DNA methyltransferase
DNMT1 protein
Histone H3
Histone methyltransferase
Histones - metabolism
Life Sciences
Molecular Dynamics Simulation
Nucleotide sequence
Research Paper
Ubiquitin
Ubiquitination
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Summary:DNMT1 is a DNA methyltransferase that catalyzes and maintains methylation in CpG dinucleotides. It blocks the entrance of DNA into the catalytic pocket via the replication foci targeting sequence (RFTS) domain. Recent studies have shown that an H3-tail-conjugated two-mono-ubiquitin mark (H3Ub2) activates DNMT1 by binding to the RFTS domain. However, the activation mechanism of DNMT1 remains unclear. In this work, we combine various sampling methods of extensive simulations, including conventional molecular dynamics, Gaussian-accelerated molecular dynamics, and coarse-grained molecular dynamics, to elucidate the activation mechanism of DNMT1. Geometric and energy analyses show that binding of H3Ub2 to the RFTS domain of DNMT1 results in the bending of the α4-helix in the RFTS domain at approximately 30°–35°, and the RFTS domain rotates ∼20° anti-clockwise and moves ∼3 Å away from the target recognition domain (TRD). The hydrogen-bonding network at the RFTS-TRD interface is significantly disrupted, implying that the RFTS domain is dissociated from the catalytic core, which contributes to activating the auto-inhibited conformation of DNMT1. These results provide structural and dynamic evidence for the role of H3Ub2 in regulating the catalytic activity of DNMT1.
ISSN:1674-7305
1869-1889
DOI:10.1007/s11427-021-2179-8