Histone H3 Inhibits Ubiquitin-Ubiquitin Intermolecular Interactions to Enhance Binding to DNA Methyl Transferase 1. Issue 2 (30th January 2022)

• Record Type: Journal Article
• Authors: Yasuda, Takunori; Morita, Rikuri; Shigeta, Yasuteru; Harada, Ryuhei
• Is Part Of: Journal of molecular biology. Volume 434:Issue 2(2022)
• Publication Date: 2022-01-30
• Subjects: Dnmt1 DNA methyl transferase 1 -- H3T histone H3 tail -- MD molecular dynamics -- RFTS replication foci targeting sequence -- ITC isothermal titration calorimetry -- RC reaction coordinate -- IP inner product -- MSM Markov state model -- PMF potential mean forces; DNA methyltransferase 1 -- mono-ubiquitinated histone H3 tail -- molecular dynamics simulation -- activation mechanism; Molecular biology -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Bacteriology -- Periodicals; Molecular Biology -- Periodicals; Biochemistry -- Periodicals; Biologie moléculaire -- Périodiques; Biologie -- Périodiques; Biochimie -- Périodiques; Moleculaire biologie; Biochemistry; Biology; Molecular biology; Periodicals; 572.805
• DOI: 10.1016/j.jmb.2021.167371
• Languages: English
• ISSNs: 0022-2836

Abstract

Graphical abstract: Highlights: Dnmt1 is activated by two-mono-ubiquitinated histone H3 tail (H3T). The activation mechanism of Dnmt1 has been determined using MD simulations. The presence of H3T makes ubiquitin-ubiquitin intermolecular contacts weaker. The structural properties of H3T modulate the ubiquitin-ubiquitin interaction. H3T inhibits the ubiquitin-ubiquitin interaction for binding to Dnmt1. Abstract: DNA methyltransferase 1 (Dnmt1) is crucial for cell maintenance and preferentially methylates hemimethylated DNA. Recently, a study revealed that Dnmt1 is timely and site-specifically activated by several types of two-mono-ubiquitinated histone H3 tails (H3Ts). However, the molecular mechanism of Dnmt1 activation has not yet been determined, in addition to the role of H3T. Based on experimental data, two-mono-ubiquitinated H3Ts activate Dnmt1 by binding, with different binding affinities. In contrast, ubiquitin molecules unlinked with H3T do not bind to Dnmt1. Despite the existence of experimental data, it is unclear why the binding affinities for Dnmt1 are different. To obtain new insights into the activation mechanism of Dnmt1, we performed all-atom molecular dynamics (MD) simulations on three systems: (1) K14/K18, (2) K14/K23 mono-ubiquitinated H3Ts, and (3) two ubiquitin molecules unlinked with H3T. As an analysis of our MD trajectories, these ubiquitylation patterns modulated ubiquitin-ubiquitin intermolecular interactions. More specifically, the intermolecular contacts between a pair of ubiquitin molecules linked with H3T became weak in the presence of H3T, indicating that H3T makes a cleft between them to inhibit their intermolecular interactions. For these three systems, the intermolecular interactions between the ubiquitin molecules calculated by our MD simulations are in good agreement with the binding affinities for Dnmt1 experimentally measured in a previous study. Therefore, we conclude that H3T acts as a spacer to inhibit ubiquitin-ubiquitin intermolecular interactions, enhancing binding to Dnmt1.