biostudies-literatureXu THNCI NIH HHS151-155https://www.ebi.ac.uk/biostudies/studies/S-EPMC7540737biostudies-literatureUnknown586(7827)CpG methylation by de novo DNA methyltransferases (DNMTs) 3A and 3B is essential for mammalian development and differentiation and is frequently dysregulated in cancer¹. These two DNMTs preferentially bind to nucleosomes, yet cannot methylate the DNA wrapped around the nucleosome core², and they favour the methylation of linker DNA at positioned nucleosomes^3,4. Here we present the cryo-electron microscopy structure of a ternary complex of catalytically competent DNMT3A2, the catalytically inactive accessory subunit DNMT3B3 and a nucleosome core particle flanked by linker DNA. The catalytic-like domain of the accessory DNMT3B3 binds to the acidic patch of the nucleosome core, which orients the binding of DNMT3A2 to the linker DNA. The steric constraints of tNatureStructure of nucleosome-bound DNA methyltransferases DNMT3A and DNMT3B.PMC7540737R50 CA243878R35 CA209859Zhou XELiang GLiu MMelcher KZhao GJones PAXu THXu HEfalseStructure of nucleosome-bound DNA methyltransferases DNMT3A and DNMT3B.CpG methylation by de novo DNA methyltransferases (DNMTs) 3A and 3B is essential for mammalian development and differentiation and is frequently dysregulated in cancer¹. These two DNMTs preferentially bind to nucleosomes, yet cannot methylate the DNA wrapped around the nucleosome core², and they favour the methylation of linker DNA at positioned nucleosomes^3,4. Here we present the cryo-electron microscopy structure of a ternary complex of catalytically competent DNMT3A2, the catalytically inactive accessory subunit DNMT3B3 and a nucleosome core particle flanked by linker DNA. The catalytic-like domain of the accessory DNMT3B3 binds to the acidic patch of the nucleosome core, which orients the binding of DNMT3A2 to the linker DNA. The steric constraints of t2020-01-01T00:00:00Z2020 Oct2026-05-09T00:39:13.882Z2025-02-19T02:13:14.99ZS-EPMC75407373296827510.1038/s41586-020-2747-1