Abstract 1386 Suppress the dominant-negative effect of DNMT3A mutants in leukemogenesis

• DOI: 10.1016/j.jbc.2024.106166
• Publication Date: 2024-03-25T21:50:56Z
• Authors: Jikui Song; Jiuwei Lu; Yiran Guo; Jianbin Chen; Jiekai Yin; Yinsheng Wang; Gang Wang

DNA methyltransferase DNMT3A-mediated de novo methylation critically regulates epigenomic and transcriptomic patterning during development. The hotspot DNMT3A mutations at the site of Arg822 (R882) give rise to a dominant-negative effect in hypomethylation cells, which turn contributes pathogenesis acute myeloid leukemia (AML) other human diseases. To decipher mechanism underlying dominant R882 mutations, we perform structural, biochemical, cellular characterizations wild-type R882-mutated homo-oligomers. Our study uncover large enthalpy-entropy compensation associated with formation one oligomeric interface (a.k.a. RD interface), confers high sensitivity assembly amino acid variation within this interface, distinct behavior between closely related DNMT3B. Mechanistically, introduce subtle structural dynamic perturbations resulting shift toward macro-oligomeric forms. Formation macro-oligomers lead reduced binding chromatin association, underpins effects mutants hypomethylation. Taking advantage DNMT3B, DNMT3B-converting effectively inhibits oligomerization-promoting mutants. In fine-tuning oligomerization by rescue mutant leads increased association genomic methylation, offsets growth TF-1 cells conferred disease Together, provides mechanistic insights into mutation-triggered AML identifies strategy suppress negative leukemogenesis. This work was supported NIH grants (R35GM119721 J.S, R01 CA215284 CA211336 G.G.W, R35 ES031707 Y.W.) University California Cancer Research Coordinating Committee (UC CRCC) grant (CRR-20-634140) J.S. G.G.W. is American Society (ACS) Scholar Leukemia & Lymphoma (LLS) Scholar.