ArticleNature communications2024
Structure-guided functional suppression of AML-associated DNMT3A hotspot mutations.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 16 citations in OpenAlex.
- Multidomain interaction governs the filamentous assembly of the dominant-negative DNMT3A R882H mutant.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Molecular basis for the inhibition of de novo DNA methylation by TCL1A.Nature communications · 2026Article
- Early Driver, Late Bystander: Stage-Specific Roles of DNMT3A R882 Mutations Unveiled in Human AML.Cancer discovery · 2026Article
- A role of protein conformational dynamics in mammalian DNA methylation.Structural dynamics (Melville, N.Y.) · 2026Review
- Structural insight into hierarchical DNMT3A autoinhibition and its dysregulation in disease.Nature communications · 2026Article
- Comprehensive profiling of CRISPR/dCas9 epigenome editors indicates a complex link between on and off target effects.Genome biology · 2026Article
- Mechanisms of DNMT3A-3L-mediated de novo DNA methylation on chromatin.Nature structural & molecular biology · 2026Article
- RUNX1A isoform is overexpressed in acute myeloid leukemia and is associated with FLT3 internal tandem duplications.Cancer gene therapy · 2025Article
- BAHCC1 binds H4K20me1 to facilitate the MCM complex loading and DNA replication.Nature communications · 2025Article
- Pharmacologic degradation of WDR5 suppresses oncogenic activities of SS18::SSX and provides a therapeutic of synovial sarcoma.Science advances · 2025Article
- Significance of targeting DNMT3A mutations in AML.Annals of hematology · 2025Review
- Using human disease mutations to understand de novo DNA methyltransferase function.Biochemical Society transactions · 2024Review
- Epigenetic modifications in hematopoietic ecosystem: a key tuner from homeostasis to acute myeloid leukemia.Blood science (Baltimore, Md.) · 2024Review
- EZH2 PROTACs target EZH2- and FOXM1-associated oncogenic nodes, suppressing breast cancer cell growth.Oncogene · 2024Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
DNA methyltransferases DNMT3A- and DNMT3B-mediated DNA methylation critically regulate epigenomic and transcriptomic patterning during development. The hotspot DNMT3A mutations at the site of Arg822 (R882) promote polymerization, leading to aberrant DNA methylation that may contribute to the pathogenesis of acute myeloid leukemia (AML). However, the molecular basis underlying the mutation-induced functional misregulation of DNMT3A remains unclear. Here, we report the crystal structures of the DNMT3A methyltransferase domain, revealing a molecular basis for its oligomerization behavior distinct to DNMT3B, and the enhanced intermolecular contacts caused by the R882H or R882C mutation. Our biochemical, cellular, and genomic DNA methylation analyses demonstrate that introducing the DNMT3B-converting mutations inhibits the R882H-/R882C-triggered DNMT3A polymerization and enhances substrate access, thereby eliminating the dominant-negative effect of the DNMT3A R882 mutations in cells. Together, this study provides mechanistic insights into DNMT3A R882 mutations-triggered aberrant oligomerization and DNA hypomethylation in AML, with important implications in cancer therapy.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.