ArticleNucleic acids research2018
The DNMT3A R882H mutant displays altered flanking sequence preferences.
Article in Nucleic acids research, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 49 citations in OpenAlex.
- Clonal hematopoiesis-associated DNMT3A mutations derepress bivalent Polycomb target genes and enhance macrophage migration.bioRxiv : the preprint server for biology · 2026Article
- DNMT3A in cancer: from epigenetic writer to oncogenic driver.Clinical epigenetics · 2026Review
- A CADASIL NOTCH3 mutation leads to clonal hematopoiesis and expansion of Dnmt3a-R878H hematopoietic clones.Leukemia · 2025Article
- Structure-guided functional suppression of AML-associated DNMT3A hotspot mutations.Nature communications · 2024Article
- Structural basis for the allosteric regulation and dynamic assembly of DNMT3B.Nucleic acids research · 2023Article
- Base Editor Scanning Reveals Activating Mutations of DNMT3A.ACS chemical biology · 2023Article
- Identification of three novel DNMT3A mutations with compromising methylation capacity in human acute myeloid leukaemia.Molecular biology reports · 2022Article
- Cell origin-dependent cooperativity of mutant Dnmt3a and Npm1 in clonal hematopoiesis and myeloid malignancy.Blood advances · 2022Article
- Methylation of recombinant mononucleosomes by DNMT3A demonstrates efficient linker DNA methylation and a role of H3K36me3.Communications biology · 2022Article
- Enzymology of Mammalian DNA Methyltransferases.Advances in experimental medicine and biology · 2022Article
- Genetic Studies on Mammalian DNA Methyltransferases.Advances in experimental medicine and biology · 2022Article
- Spontaneous arising of a lymphoblastoid B-cell line harbouring a pre-leukemic DNMT3A mutation in acute myeloid leukaemia cell culture.Journal of cellular and molecular medicine · 2021Article
- Oridonin inhibits DNMT3A R882 mutation-driven clonal hematopoiesis and leukemia by inducing apoptosis and necroptosis.Cell death discovery · 2021Article
- Structural and biochemical insight into the mechanism of dual CpG site binding and methylation by the DNMT3A DNA methyltransferase.Nucleic acids research · 2021Article
- Alterations toCancer research · 2021Review
- Flanking sequence preference modulates de novo DNA methylation in the mouse genome.Nucleic acids research · 2021Article
- Complex DNA sequence readout mechanisms of the DNMT3B DNA methyltransferase.Nucleic acids research · 2020Article
- DNA sequence-dependent activity and base flipping mechanisms of DNMT1 regulate genome-wide DNA methylation.Nature communications · 2020Article
- Comprehensive structure-function characterization of DNMT3B and DNMT3A reveals distinctive de novo DNA methylation mechanisms.Nature communications · 2020Article
- Structural basis for impairment of DNA methylation by the DNMT3A R882H mutation.Nature communications · 2020Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The DNMT3A R882H mutation is frequently observed in acute myeloid leukemia (AML). It is located in the subunit and DNA binding interface of DNMT3A and has been reported to cause a reduction in activity and dominant negative effects. We investigated the mechanistic consequences of the R882H mutation on DNMT3A showing a roughly 40% reduction in overall DNA methylation activity. Biochemical assays demonstrated that R882H does not change DNA binding affinity, protein stability or subnuclear distribution of DNMT3A. Strikingly, DNA methylation experiments revealed pronounced changes in the flanking sequence preference of the DNMT3A-R882H mutant. Based on these results, different DNA substrates with selected flanking sequences were designed to be favored or disfavored by R882H. Kinetic analyses showed that the R882H favored substrate was methylated by R882H with 45% increased rate when compared with wildtype DNMT3A, while methylation of the disfavored substrate was reduced 7-fold. Our data expand the model of the potential carcinogenic effect of the R882H mutation by showing CpG site specific activity changes. This result suggests that R882 is involved in the indirect readout of flanking sequence preferences of DNMT3A and it may explain the particular enrichment of the R882H mutation in cancer patients by revealing mutation specific effects.
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Registered trials
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