1. A chemical probe targeting the PWWP domain alters NSD2 nucleolar localization
- Author
-
Marcus A. Cheek, Aiping Dong, Renato Ferreira de Freitas, Dalia Barsyte-Lovejoy, Aliakbar Khalili Yazdi, Jinrong Min, Fengling Li, Victoria Vu, Albina Bolotokova, Lindsey I. James, Jack Greenblatt, Naimee Mehta, Irina K. Popova, David Dilworth, Ming Lei, Raquel Arminda Carvalho Machado, Ronan P Hanley, David Y Nie, Matthieu Schapira, Mengqi Zhou, Elisa Gibson, Cheryl H. Arrowsmith, Michael-Christopher Keogh, Suzanne Ackloo, Matthew R. Marunde, Mona Alqazzaz, Dmitri Kireev, Nathan W. Hall, Peter Brown, Abdellah Allali-Hassani, Sina Kazemzadeh, Edyta Marcon, Tigran M. Abramyan, Dominic D G Owens, Yanli Liu, Magdalena M. Szewczyk, Matthew J. Meiners, Irene Chau, Su Qin, and Masoud Vedadi
- Subjects
Gene isoform ,Methyltransferase ,Nucleolus ,Lysine ,Methylation ,Article ,03 medical and health sciences ,0302 clinical medicine ,Protein Domains ,Molecular Biology ,030304 developmental biology ,chemistry.chemical_classification ,0303 health sciences ,biology ,Chemistry ,Histone-Lysine N-Methyltransferase ,Cell Biology ,Nucleosomes ,Chromatin ,Cell biology ,Repressor Proteins ,Histone ,Enzyme ,Molecular Probes ,030220 oncology & carcinogenesis ,biology.protein ,Multiple Myeloma ,Cell Nucleolus - Abstract
Nuclear receptor-binding SET domain-containing 2 (NSD2) is the primary enzyme responsible for the dimethylation of lysine 36 of histone 3 (H3K36), a mark associated with active gene transcription and intergenic DNA methylation. In addition to a methyltransferase domain, NSD2 harbors two proline-tryptophan-tryptophan-proline (PWWP) domains and five plant homeodomains (PHDs) believed to serve as chromatin reading modules. Here, we report a chemical probe targeting the N-terminal PWWP (PWWP1) domain of NSD2. UNC6934 occupies the canonical H3K36me2-binding pocket of PWWP1, antagonizes PWWP1 interaction with nucleosomal H3K36me2 and selectively engages endogenous NSD2 in cells. UNC6934 induces accumulation of endogenous NSD2 in the nucleolus, phenocopying the localization defects of NSD2 protein isoforms lacking PWWP1 that result from translocations prevalent in multiple myeloma (MM). Mutations of other NSD2 chromatin reader domains also increase NSD2 nucleolar localization and enhance the effect of UNC6934. This chemical probe and the accompanying negative control UNC7145 will be useful tools in defining NSD2 biology.
- Published
- 2021