Abstract 1078: The nucleosomal acidic patch helps anchor of de novo DNA methyltransferase DNMT3A2/3B3 complex

Abstract

Abstract CpG methylation by de novo DNA methyltransferases (DNMT) 3A and 3B is essential for mammalian development and differentiation, and is frequently dysregulated in cancer. DNMT3s preferentially bind nucleosomes yet can not methylate the DNA wrapped around the nucleosome core, and favor the methylation of linker DNA at positioned nucleosomes. Here we present the cryo-EM structure of a ternary complex of catalytically active DNMT3A2, the catalytically inactive accessory subunit DNMT3B3, and a nucleosome core particle flanked with linker DNA. We find that the catalytic-like domain (CLD) of the accessory DNMT3B3 binds the acidic patch of the nucleosome core, which orients the binding of the catalyticaly active DNMT3A2 to linker DNA. The sterical constraints of this arrangement suggest that nucleosomal DNA must be moved relative to the nucleosome core for de novo methylation to occur. Citation Format: Ting-Hai Xu, Minmin Liu, Edward Zhou, Gangning Liang, Eric H. Xu, Karsten Melcher, Peter A. Jones. The nucleosomal acidic patch helps anchor of de novo DNA methyltransferase DNMT3A2/3B3 complex [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1078.