The N-terminal region of DNMT3A engages the nucleosome surface to aid chromatin recruitment

DNA methyltransferase 3 (DNMT3A) plays a critical role in establishing and maintaining DNA methylation patterns in vertebrates. Properly positioned methylation ensures normal cellular function and is both tissue-specific and heritable. Aberrant DNA methylation patterns are associated with various disorders, including cancer, as well as developmental and neurological diseases. DNMT3A1, the focus of this study, is a key methyltransferase responsible for establishing these patterns.

DNA methyltransferases are recruited to chromatin via nucleosomes, which act as landing platforms, utilising post-translational modifications (PTMs) as signals to guide specific methyltransferases. However, the structural details and mechanisms underlying this process remain poorly understood. In this study, researchers at the Wilson Lab investigated how DNMT3A1 interacts with two modified nucleosomes, H2AK119ub and H3K36me2.

A cryo-EM structure of the full-length DNMT3A1-DNMT3L complex bound to an H2AK119ub-modified nucleosome revealed that DNMT3A1’s ubiquitin-dependent recruitment (UDR) motif extensively interacts with H2AK119ub and forms extensive contacts with the nucleosome surface. This robust binding mechanism sheds light on previously unexplained disease-associated mutations that disrupt this interaction. The UDR domain also facilitates binding to nucleosomes modified with H3K36me2.

Interestingly, while H2AK119ub enhances DNMT3A1 recruitment, it does not lead to increased methylation activity, unlike H3K36me2, which significantly stimulates methylation.

This study provides critical insights into DNMT3A1 recruitment, emphasising the importance of its multivalent binding to histone modifications and the nucleosome surface.