Mutations in DNA Methyltransferase (DNMT3A) Observed in Acute Myeloid Leukemia Patients Disrupt Processive Methylation

Background: De novo DNA methyltransferase 3A is mutated in acute myeloid leukemia (AML) patients. Results: AML mutations disrupt DNMT3A tetramerization and the processive methylation of human promoters in vitro. Conclusion: DNMT3A oligomeric interfaces control processivity, which may alter methylation patterns in AML patients. Significance: DNMT3A provides a plausible explanation for changes in epigenetic regulation in AML patients. DNA methylation is a key regulator of gene expression and changes in DNA methylation occur early in tumorigenesis. Mutations in the de novo DNA methyltransferase gene, DNMT3A, frequently occur in adult acute myeloid leukemia patients with poor prognoses. Most of the mutations occur within the dimer or tetramer interface, including Arg-882. We have identified that the most prevalent mutation, R882H, and three additional mutants along the tetramer interface disrupt tetramerization. The processive methylation of multiple CpG sites is disrupted when tetramerization is eliminated. Our results provide a possible mechanism that accounts for how DNMT3A mutations may contribute to oncogenesis and its progression.

• Publication year

  2012

• Venue

  Journal of Biological Chemistry

• Publication date

  2012-06-21

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/jbc.M112.366625PMID 22722925PMCID PMC3438927
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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