A chemical probe targeting the PWWP domain alters NSD2 nucleolar localization

Dilworth，David1,16; Hanley，Ronan P.2,15; Ferreira de Freitas，Renato1,9; Allali-Hassani，Abdellah1,10; Zhou，Mengqi1,5; Mehta，Naimee2,12; Marunde，Matthew R.3; Ackloo，Suzanne1; Carvalho Machado，Raquel Arminda1; Khalili Yazdi，Aliakbar1; Owens，Dominic D.G.1; Vu，Victoria1; Nie，David Y.1,8; Alqazzaz，Mona1; Marcon，Edyta4; Li，Fengling1; Chau，Irene1; Bolotokova，Albina1; Qin，Su1,13; Lei，Ming1,5; Liu，Yanli1,11; Szewczyk，Magdalena M.1; Dong，Aiping1; Kazemzadeh，Sina2; Abramyan，Tigran2,14; Popova，Irina K.3; Hall，Nathan W.3; Meiners，Matthew J.3; Cheek，Marcus A.3; Gibson，Elisa1; Kireev，Dmitri2; Greenblatt，Jack F.4; Keogh，Michael C.3; Min，Jinrong1,5; Brown，Peter J.1; Vedadi，Masoud1,6; Arrowsmith，Cheryl H.1,7; Barsyte-Lovejoy，Dalia1,6; James，Lindsey I.2; Schapira，Matthieu1,6

2021

10.1038/s41589-021-00898-0

Nature Chemical Biology   影响因子和分区

1552-4450

1552-4469

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. [Figure not available: see fulltext.].

SCI

英语

NI期刊

其他

Genome Canada through Ontario Genomics Institute[OGI-196] ; EU/EFPIA/OICR/McGill/KTH/Diamond Innovative Medicines Initiative 2 Joint Undertaking (EUbOPEN grant)[875510] ; Wellcome[106169/ZZ14/Z] ; National Cancer Institute, NIH[R01CA242305] ; NSERC[RGPIN-2019-04416] ; NIH["R44GM117683","R44GM116584"] ; Cancer Research Society[25418] ; National Science Foundation[CHE-1726291] ; National Institute of Mental Health's Psychoactive Drug Screening Program[HHSN-271-2018-00023-C]

Biochemistry & Molecular Biology

Biochemistry & Molecular Biology

WOS:000718756300001

NATURE PORTFOLIO

2-s2.0-85118966766

Scopus

1.Structural Genomics Consortium,University of Toronto,Toronto,Canada
2.Center for Integrative Chemical Biology and Drug Discovery,Division of Chemical Biology and Medicinal Chemistry,UNC Eshelman School of Pharmacy,University of North Carolina at Chapel Hill,Chapel Hill,United States
3.EpiCypher Inc.,Durham,United States
4.Donnelly Centre,University of Toronto,Toronto,Canada
5.Hubei Key Laboratory of Genetic Regulation and Integrative Biology,School of Life Sciences,Central China Normal University,Wuhan,China
6.Department of Pharmacology and Toxicology,University of Toronto,Toronto,Canada
7.Princess Margaret Cancer Centre and Department of Medical Biophysics,University of Toronto,Toronto,Canada
8.Department of Medical Biophysics,University of Toronto,Toronto,Canada
9.Centro de Ciências Naturais e Humanas,Universidade Federal do ABC,Rua Arcturus 3,São Bernardo do Campo,Brazil
10.Incyte,Wilmington,United States
11.College of Pharmaceutical Sciences,Soochow University,Suzhou,China
12.Nurix Therapeutics,San Francisco,United States
13.Life Science Research Center,Southern University of Science and Technology,Shenzhen,China
14.Atomwise,San Francisco,United States
15.C4 Therapeutics,Watertown,United States
16.BlueRock Therapeutics,Toronto,Canada

Dilworth，David,Hanley，Ronan P.,Ferreira de Freitas，Renato,et al. A chemical probe targeting the PWWP domain alters NSD2 nucleolar localization[J]. Nature Chemical Biology,2021.

Dilworth，David.,Hanley，Ronan P..,Ferreira de Freitas，Renato.,Allali-Hassani，Abdellah.,Zhou，Mengqi.,...&Schapira，Matthieu.(2021).A chemical probe targeting the PWWP domain alters NSD2 nucleolar localization.Nature Chemical Biology.

Dilworth，David,et al."A chemical probe targeting the PWWP domain alters NSD2 nucleolar localization".Nature Chemical Biology (2021).