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A chemical probe targeting the PWWP domain alters NSD2 nucleolar localization.


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.

SUBMITTER: Dilworth D 

PROVIDER: S-EPMC9189931 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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A chemical probe targeting the PWWP domain alters NSD2 nucleolar localization.

Dilworth David D   Hanley Ronan P RP   Ferreira de Freitas Renato R   Allali-Hassani Abdellah A   Zhou Mengqi M   Mehta Naimee N   Marunde Matthew R MR   Ackloo Suzanne S   Carvalho Machado Raquel Arminda RA   Khalili Yazdi Aliakbar A   Owens Dominic D G DDG   Vu Victoria V   Nie David Y DY   Alqazzaz Mona M   Marcon Edyta E   Li Fengling F   Chau Irene I   Bolotokova Albina A   Qin Su S   Lei Ming M   Liu Yanli Y   Szewczyk Magdalena M MM   Dong Aiping A   Kazemzadeh Sina S   Abramyan Tigran T   Popova Irina K IK   Hall Nathan W NW   Meiners Matthew J MJ   Cheek Marcus A MA   Gibson Elisa E   Kireev Dmitri D   Greenblatt Jack F JF   Keogh Michael-C MC   Min Jinrong J   Brown Peter J PJ   Vedadi Masoud M   Arrowsmith Cheryl H CH   Barsyte-Lovejoy Dalia D   James Lindsey I LI   Schapira Matthieu M  

Nature chemical biology 20211115 1


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) domai  ...[more]

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