Molecular basis of nucleosomal H3K36 methylation by NSD methyltransferases
- 23 December 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature
- Vol. 590 (7846), 498-503
- https://doi.org/10.1038/s41586-020-03069-8
Abstract
Histone methyltransferases of the nuclear receptor-binding SET domain protein (NSD) family, including NSD1, NSD2 and NSD3, have crucial roles in chromatin regulation and are implicated in oncogenesis1,2. NSD enzymes exhibit an autoinhibitory state that is relieved by binding to nucleosomes, enabling dimethylation of histone H3 at Lys36 (H3K36)3,4,5,6,7. However, the molecular basis that underlies this mechanism is largely unknown. Here we solve the cryo-electron microscopy structures of NSD2 and NSD3 bound to mononucleosomes. We find that binding of NSD2 and NSD3 to mononucleosomes causes DNA near the linker region to unwrap, which facilitates insertion of the catalytic core between the histone octamer and the unwrapped segment of DNA. A network of DNA- and histone-specific contacts between NSD2 or NSD3 and the nucleosome precisely defines the position of the enzyme on the nucleosome, explaining the specificity of methylation to H3K36. Intermolecular contacts between NSD proteins and nucleosomes are altered by several recurrent cancer-associated mutations in NSD2 and NSD3. NSDs that contain these mutations are catalytically hyperactive in vitro and in cells, and their ectopic expression promotes the proliferation of cancer cells and the growth of xenograft tumours. Together, our research provides molecular insights into the nucleosome-based recognition and histone-modification mechanisms of NSD2 and NSD3, which could lead to strategies for therapeutic targeting of proteins of the NSD family.Keywords
This publication has 42 references indexed in Scilit:
- Landscape of somatic mutations and clonal evolution in mantle cell lymphomaProceedings of the National Academy of Sciences of the United States of America, 2013
- A Bayesian View on Cryo-EM Structure DeterminationJournal of Molecular Biology, 2012
- NSD2 Links Dimethylation of Histone H3 at Lysine 36 to Oncogenic ProgrammingMolecular Cell, 2011
- The Structure of NSD1 Reveals an Autoregulatory Mechanism Underlying Histone H3K36 MethylationOnline Journal of Public Health Informatics, 2011
- Structure of RCC1 chromatin factor bound to the nucleosome core particleNature, 2010
- PHENIX: a comprehensive Python-based system for macromolecular structure solutionActa crystallographica. Section D, Structural biology, 2010
- MolProbity: all-atom structure validation for macromolecular crystallographyActa crystallographica. Section D, Structural biology, 2009
- The Target of the NSD Family of Histone Lysine Methyltransferases Depends on the Nature of the SubstrateOnline Journal of Public Health Informatics, 2009
- UCSF Chimera?A visualization system for exploratory research and analysisJournal of Computational Chemistry, 2004
- New DNA sequence rules for high affinity binding to histone octamer and sequence-directed nucleosome positioningJournal of Molecular Biology, 1998