Cancer Cell
Volume 25, Issue 4, 14 April 2014, Pages 442-454
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Article
The R882H DNMT3A Mutation Associated with AML Dominantly Inhibits Wild-Type DNMT3A by Blocking Its Ability to Form Active Tetramers

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Highlights

  • AML cases with DNMT3A mutations at R882 exhibit focal hypomethylation

  • R882H DNMT3A is a dominant-negative inhibitor of WT DNMT3A

  • WT DNMT3A forms stable, active homotetramers

  • R882H DNMT3A dominantly disrupts DNMT3A tetramerization

Summary

Somatic mutations in DNMT3A, which encodes a de novo DNA methyltransferase, are found in ∼30% of normal karyotype acute myeloid leukemia (AML) cases. Most mutations are heterozygous and alter R882 within the catalytic domain (most commonly R882H), suggesting the possibility of dominant-negative consequences. The methyltransferase activity of R882H DNMT3A is reduced by ∼80% compared with the WT enzyme. In vitro mixing of WT and R882H DNMT3A does not affect the WT activity, but coexpression of the two proteins in cells profoundly inhibits the WT enzyme by disrupting its ability to homotetramerize. AML cells with the R882H mutation have severely reduced de novo methyltransferase activity and focal hypomethylation at specific CpGs throughout AML cell genomes.

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