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

Abstract

Significance DNMT3A R882H (DNMT3AR882H) mutation is a hot-spot mutation in acute myeloid leukemia and developmental disorders. Previous studies have identified that DNMT3AR882H promotes the formation of high-order protein oligomers, giving rise to a dominant-negative effect on DNMT3A-mediated DNA methylation. This study reports the structure and mechanism for the dynamic assembly of wild-type DNMT3A homo-oligomer and the filamentous DNMT3AR882H polymer, revealing a role of the autoinhibition, mediated by regulatory Pro-Trp-Trp-Pro and ATRX-DNMT3-DNMT3L domains, in potentiating the filamentous assembly of DNMT3AR882H. Disrupting the autoinhibitory interaction facilitates the transition of DNMT3AR882H toward low-order oligomeric assembly. This study opens a window for development of effective strategies against DNMT3AR882H-associated diseases.