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AML-Associated Mutations in DNA Methyltransferase DNMT3A

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Abstract

In mammals, DNA methylation is an essential epigenetic modification necessary for the maintenance of genome stability, regulation of gene expression, and other processes. Carcinogenesis is accompanied by multiple changes in the DNA methylation pattern and DNA methyltransferase (DNMT) genes; these changes are often associated with poor disease prognosis. Human DNA methyltransferase DNMT3A is responsible for de novo DNA methylation. Missense mutations in the DNMT3A gene occur frequently at the early stages of tumor development and are often observed in hematologic malignances, especially in acute myeloid leukemia (AML), with a prevalence of the R882H mutation. This mutation is the only one that has been extensively studied using both model DNA substrates and cancer cell lines. Biochemical characterization of other DNMT3A mutants is necessary to assess their potential effects on the DNMT3A functioning. In this review, we describe DNMT3A mutations identified in AML with special emphasis on the missense mutations in the DNMT3A catalytic domain. The impact of R882H and less common missense mutations on the DNMT3A activity toward model DNA substrates and in cancer cell lines is discussed together with the underlying molecular mechanisms. Understanding general features of these mechanisms will be useful for further development of novel approaches for early diagnostics of hematologic diseases and personalized cancer therapy.

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Abbreviations

AML:

acute myeloid leukemia

ADD domain:

ATRX-DNMT3A/3B-DNMT3L domain

AdoMet:

S-adenosyl-L-methionine

AMLL:

acute mixed-lineage leukemia

CD:

catalytic domain

DNMT:

DNA methyltransferase

PWWP domain:

Pro-Trp-Trp-Pro domain

MDS:

myelodysplastic syndrome

TRD:

target recognition domain

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Funding

This work was supported by the Russian Foundation for Basic Research (project no. 19-04-00533-a).

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Authors and Affiliations

  1. Faculty of Chemistry, Lomonosov Moscow State University, 119991, Moscow, Russia

    Dariya A. Khrabrova & Elizaveta S. Gromova

  2. Blokhin National Medical Research Center of Oncology, Ministry of Health of the Russian Federation, 115478, Moscow, Russia

    Marianna G. Yakubovskaya

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  1. Dariya A. Khrabrova
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  2. Marianna G. Yakubovskaya
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  3. Elizaveta S. Gromova
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Correspondence to Dariya A. Khrabrova.

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The authors declare no conflict of interest in financial or any other sphere. This article does not contain description of studies with human participants or animals performed by any of the authors.

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Khrabrova, D.A., Yakubovskaya, M.G. & Gromova, E.S. AML-Associated Mutations in DNA Methyltransferase DNMT3A. Biochemistry Moscow 86, 307–318 (2021). https://doi.org/10.1134/S000629792103007X

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