Structure-guided functional suppression of AML-associated DNMT3A hotspot mutations

Jiuwei Lu, Yiran Guo, Jiekai Yin, Jianbin Chen, Yinsheng Wang, Gang Greg Wang () and Jikui Song ()
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Jiuwei Lu: University of California
Yiran Guo: Duke University School of Medicine
Jiekai Yin: University of California
Jianbin Chen: University of California
Yinsheng Wang: University of California
Gang Greg Wang: Duke University School of Medicine
Jikui Song: University of California

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47398-y

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