Multidomain interaction governs the filamentous assembly of the dominant-negative DNMT3A R882H mutant

• 成果类型: Article
• 署名作者: Chen, Jianbin; Lu, Jiuwei; Long, Zhixu; Yoon, Sol; Fukunaga, Megan; Song, Jikui
• 署名单位: University of California System; University of California Riverside
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2609226123
• 发表日期: 2026-09-01
• 页码: e2609226123
• 关键词: DNMT3A; DNMT3A R882H; polymerization; dna methylation; DE-NOVO METHYLATION; DNA METHYLTRANSFERASES DNMT3A; structural basis; IMMUNODEFICIENCY SYNDROME; mutations; gene; nucleosome; domain; oligomerization; RECOGNITION

摘要

DNA methyltransferase DNMT3A-mediated de novo DNA methylation is important for proper regulation of gene expression and genomic stability in development. The DNMT3A R882H (DNMT3AR882H) mutation, a hot-spot mutation in acute myeloid leukemia and developmental disorders, exerts a dominant-negative effect in DNMT3A-mediated DNA methylation through promoting high-order protein assembly. However, due to the lack of structural knowledge on DNMT3A homo-oligomers, the mechanism behind wild-type DNMT3A (DNMT3AWT) and DNMT3AR882H polymerization remains unclear. Here, we report the single-particle cryo-EM structures of homo-oligomeric DNMT3AWT and filamentous DNMT3AR882H, revealing the role of the regulatory Pro-Trp-Trp-Pro (PWWP) and ATRX-DNMT3-DNMT3L (ADD) domains of DNMT3A in their dynamic assembly. While the oligomeric assembly of DNMT3A is mainly driven by the well-characterized oligomer interfaces in the methyltransferase domain, the autoinhibitory interaction of the PWWP and ADD domains in DNMT3A places them in a position for intermolecular contact, thereby contributing to the filamentous assembly of DNMT3AR882H. Disrupting the autoinhibitory interaction facilitates the transition of DNMT3AR882H polymer toward the low-order oligomeric assembly, reinforcing the aggregation-attenuation effect of the previously characterized oligomer-interface mutation R676K. Together, this study uncovers a multidomain cooperated assembly mechanism for DNMT3A, with important implication in development of effective therapeutic strategies against DNMT3AR882H-associated diseases.