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

Lu, Jiuwei; Guo, Yiran; Yin, Jiekai; Chen, Jianbin; Wang, Yinsheng; Wang, Gang Greg; Song, Jikui

doi:10.1038/s41467-024-47398-y

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

Journal Article · 10 April 2024 · Nature Communications

DOI: https://doi.org/10.1038/s41467-024-47398-y · OSTI ID:2471066

^[1]; Guo, Yiran ^[2]; Yin, Jiekai ^[1]; Chen, Jianbin ^[1]; Wang, Yinsheng ^[1];

^[2];

^[1]

Univ. of California, Riverside, CA (United States)
Duke Univ., Durham, NC (United States)

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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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Advanced Light Source (ALS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2471066

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 15; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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