Next Article in Journal
4-Aminobenzoic Acid Derivatives: Converting Folate Precursor to Antimicrobial and Cytotoxic Agents
Next Article in Special Issue
Hydroxylamine Analogue of Agmatine: Magic Bullet for Arginine Decarboxylase
Previous Article in Journal
Designer Amyloid Cell-Penetrating Peptides for Potential Use as Gene Transfer Vehicles
Previous Article in Special Issue
Gender-Related Differences on Polyamine Metabolome in Liquid Biopsies by a Simple and Sensitive Two-Step Liquid-Liquid Extraction and LC-MS/MS
Open AccessArticle

Functional Analysis of DNMT3A DNA Methyltransferase Mutations Reported in Patients with Acute Myeloid Leukemia

1
Chemistry Department, Lomonosov Moscow State University, 119991 Moscow, Russia
2
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655, USA
*
Authors to whom correspondence should be addressed.
Biomolecules 2020, 10(1), 8; https://doi.org/10.3390/biom10010008
Received: 27 November 2019 / Revised: 13 December 2019 / Accepted: 15 December 2019 / Published: 18 December 2019
(This article belongs to the Special Issue Biogenic Polyamines and Related Metabolites)
In mammals, DNA methylation is necessary for the maintenance of genomic stability, gene expression regulation, and other processes. During malignant diseases progression, changes in both DNA methylation patterns and DNA methyltransferase (MTase) genes are observed. Human de novo MTase DNMT3A is most frequently mutated in acute myeloid leukemia (AML) with a striking prevalence of R882H mutation, which has been extensively studied. Here, we investigate the functional role of the missense mutations (S714C, R635W, R736H, R771L, P777R, and F752V) found in the catalytic domain of DNMT3A in AML patients. These were accordingly mutated in the murine Dnmt3a catalytic domain (S124C, R45W, R146H, R181L, P187R, and F162V) and in addition, one-site CpG-containing DNA substrates were used as a model system. The 3–15-fold decrease (S124C and P187R) or complete loss (F162V, R45W, and R146H) of Dnmt3a-CD methylation activity was observed. Remarkably, Pro 187 and Arg 146 are not located at or near the Dnmt3a functional motives. Regulatory protein Dnmt3L did not enhance the methylation activity of R45W, R146H, P187R, and F162V mutants. The key steps of the Dnmt3a-mediated methylation mechanism, including DNA binding and transient covalent intermediate formation, were examined. There was a complete loss of DNA-binding affinity for R45W located in the AdoMet binding region and for R146H. Dnmt3a mutants studied in vitro suggest functional impairment of DNMT3A during pathogenesis. View Full-Text
Keywords: DNA methyltransferase Dnmt3a; missense mutations; leukemia; DNA methylation; S-adenosyl-L-methionine; DNA-protein binding DNA methyltransferase Dnmt3a; missense mutations; leukemia; DNA methylation; S-adenosyl-L-methionine; DNA-protein binding
Show Figures

Figure 1

MDPI and ACS Style

Khrabrova, D.A.; Loiko, A.G.; Tolkacheva, A.A.; Cherepanova, N.A.; Zvereva, M.I.; Kirsanova, O.V.; Gromova, E.S. Functional Analysis of DNMT3A DNA Methyltransferase Mutations Reported in Patients with Acute Myeloid Leukemia. Biomolecules 2020, 10, 8. https://doi.org/10.3390/biom10010008

AMA Style

Khrabrova DA, Loiko AG, Tolkacheva AA, Cherepanova NA, Zvereva MI, Kirsanova OV, Gromova ES. Functional Analysis of DNMT3A DNA Methyltransferase Mutations Reported in Patients with Acute Myeloid Leukemia. Biomolecules. 2020; 10(1):8. https://doi.org/10.3390/biom10010008

Chicago/Turabian Style

Khrabrova, Daria A.; Loiko, Andrei G.; Tolkacheva, Anastasia A.; Cherepanova, Natalia A.; Zvereva, Maria I.; Kirsanova, Olga V.; Gromova, Elizaveta S. 2020. "Functional Analysis of DNMT3A DNA Methyltransferase Mutations Reported in Patients with Acute Myeloid Leukemia" Biomolecules 10, no. 1: 8. https://doi.org/10.3390/biom10010008

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Search more from Scilit
 
Search
Back to TopTop