| Literature DB >> 34782742 |
David Dilworth1,2, Ronan P Hanley3,4, Renato Ferreira de Freitas5,6, Abdellah Allali-Hassani5,7, Mengqi Zhou5,8, Naimee Mehta3,9, Matthew R Marunde10, Suzanne Ackloo5, Raquel Arminda Carvalho Machado5, Aliakbar Khalili Yazdi5, Dominic D G Owens5, Victoria Vu5, David Y Nie5,11, Mona Alqazzaz5, Edyta Marcon12, Fengling Li5, Irene Chau5, Albina Bolotokova5, Su Qin5,13, Ming Lei5,8, Yanli Liu5,14, Magdalena M Szewczyk5, Aiping Dong5, Sina Kazemzadeh3, Tigran Abramyan3,15, Irina K Popova10, Nathan W Hall10, Matthew J Meiners10, Marcus A Cheek10, Elisa Gibson5, Dmitri Kireev3, Jack F Greenblatt12, Michael-C Keogh10, Jinrong Min5,8, Peter J Brown5, Masoud Vedadi5,16, Cheryl H Arrowsmith5,17, Dalia Barsyte-Lovejoy18,19, Lindsey I James20, Matthieu Schapira21,22.
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.Entities:
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Year: 2021 PMID： 34782742 PMCID： PMC9189931 DOI： 10.1038/s41589-021-00898-0
Source DB: PubMed Journal: Nat Chem Biol ISSN： 1552-4450 Impact factor: 16.174