A Quantum Mechanics/Molecular Mechanics Study of the Catalytic Mechanism and Product Specificity of Viral Histone Lysine Methyltransferase†

ABSTRACT Haploinsufficiency of the NSD1 gene is a hallmark of Sotos syndrome, and rearrangements of this gene by translocation can cause acute myeloid leukemia. The NSD1 gene product is a SET-domain histone lysine methyltransferase that has previously been shown to interact with nuclear receptors. We describe here a novel NSD1-interacting protein, Nizp1, that contains a SCAN box, a KRAB-A domain, and four consensus C2H2-type zinc fingers preceded by a unique finger derivative, referred to herein as the C2HR motif. The C2HR motif functions to mediate protein-protein interaction with the cysteine-rich (C5HCH) domain of NSD1 in a Zn(II)-dependent fashion, and when tethered to RNA polymerase II promoters, represses transcription in an NSD1-dependent manner. Mutations of the cysteine or histidine residues in the C2HR motif abolish the interaction of Nizp1 with NSD1 and compromise the ability of Nizp1 to repress transcription. Interestingly, converting the C2HR motif into a canonical C2H2 zinc finger has a similar effect. Thus, Nizp1 contains a novel type of zinc finger motif that functions as a docking site for NSD1 and is more than just a degenerate evolutionary remnant of a C2H2 motif.

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Ab Initio Quantum Mechanical/Molecular Mechanical Molecular Dynamics Simulation of Enzyme Catalysis: The Case of Histone Lysine Methyltransferase SET7/9

The Journal of Physical Chemistry B ◽

10.1021/jp067147i ◽

2007 ◽

Vol 111 (14) ◽

pp. 3758-3764 ◽

Cited By ~ 56

Author(s):

Shenglong Wang ◽

Po Hu ◽

Yingkai Zhang

Keyword(s):

Molecular Dynamics ◽

Molecular Dynamics Simulation ◽

Ab Initio ◽

Enzyme Catalysis ◽

Dynamics Simulation ◽

Quantum Mechanical ◽

Histone Lysine ◽

Histone Lysine Methyltransferase ◽

Lysine Methyltransferase

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Prenatal nicotine exposure leads to decreased histone H3 lysine 9 (H3K9) methylation and increased p66shc expression in the neonatal pancreas

Journal of Developmental Origins of Health and Disease ◽

10.1017/s2040174421000283 ◽

2021 ◽

pp. 1-5

Author(s):

Sergio Raez-Villanueva ◽

Amrita Debnath ◽

Daniel B. Hardy ◽

Alison C. Holloway

Keyword(s):

Pancreatic Beta Cells ◽

Histone H3 ◽

Adverse Outcomes ◽

Beta Cell Apoptosis ◽

Nicotine Exposure ◽

Nicotine Treatment ◽

Histone Lysine ◽

Histone Lysine Methyltransferase ◽

Lysine Methyltransferase ◽

Prenatal Nicotine

Abstract Prenatal exposure to nicotine, tobacco’s major addictive constituent, has been shown to reduce birth weight and increases apoptosis, oxidative stress, and mitochondrial dysfunction in the postnatal pancreas. Given that upregulated levels of the pro-oxidative adapter protein p66shc is observed in growth-restricted offspring and is linked to beta-cell apoptosis, the goal of this study was to investigate whether alterations in p66shc expression underlie the pancreatic deficits in nicotine-exposed offspring. Maternal administration of nicotine in rats increased p66shc expression in the neonatal pancreas. Similarly, nicotine treatment augmented p66shc expression in INS-1E pancreatic beta cells. Increased p66shc expression was also associated with decreased histone H3 lysine 9 methylation. Finally, nicotine increased the expression of Kdm4c, a key histone lysine demethylase, and decreased Suv39h1, a critical histone lysine methyltransferase. Collectively, these results suggest that upregulation of p66shc through posttranslational histone modifications may underlie the reported adverse outcomes of nicotine exposure on pancreatic function.

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