{"doi":"10.1101/2021.03.05.433782","title":"Pharmacological targeting of a PWWP domain demonstrates cooperative control of NSD2 localization","abstract":"Abstract NSD2 is the primary enzyme responsible for the dimethylation of lysine 36 of histone 3 (H3K36me2), a mark associated with active gene transcription and intergenic DNA methylation. In addition to a methyltransferase domain, NSD2 harbors two PWWP and five PHD domains believed to serve as chromatin reading modules, but their exact function in the regulation of NSD2 activity remains underexplored. Here we report a first-in-class chemical probe targeting the N-terminal PWWP (PWWP1) domain of NSD2. UNC6934 binds potently (K d of 91 ± 8 nM) to PWWP1, antagonizes its interaction with nucleosomal H3K36me2, and selectively engages endogenous NSD2 in cells. Crystal structures show that UNC6934 occupies the canonical H3K36me2-binding pocket of PWWP1 which is juxtaposed to the DNA-binding surface. In cells, UNC6934 induces accumulation of endogenous NSD2 in the nucleolus, phenocopying the localization defects of NSD2 protein isoforms lacking PWWP1 as a result of translocations prevalent in multiple myeloma. Mutation of other NSD2 chromatin reader domains also increases NSD2 nucleolar localization, and enhances the effect of UNC6934 . Finally we identified two C-terminal nucleolar localization sequences in NSD2 that appear to drive nucleolar accumulation when one or more chromatin reader domains are disabled. These data support a model in which NSD2 chromatin engagement is achieved in a cooperative manner and subcellular localization is controlled by multiple competitive structural determinants. This chemical probe and the accompanying negative control, UNC7145 , will be useful tools in defining NSD2 biology.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":217236,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9562,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":564101,"name":"Ronan P. Hanley","orcid":null,"position":1,"is_corresponding":false},{"id":563497,"name":"Renato Ferreira de Freitas","orcid":"0000-0001-6195-4236","position":2,"is_corresponding":false},{"id":178002,"name":"Abdellah Allali‐Hassani","orcid":null,"position":3,"is_corresponding":false},{"id":635799,"name":"Mengqi Zhou","orcid":null,"position":4,"is_corresponding":false},{"id":564100,"name":"Naimee Mehta","orcid":null,"position":5,"is_corresponding":false},{"id":275702,"name":"Matthew R. Marunde","orcid":"0009-0007-5934-7200","position":6,"is_corresponding":false},{"id":277396,"name":"Suzanne Ackloo","orcid":"0000-0002-9696-1839","position":7,"is_corresponding":false},{"id":121063,"name":"Edyta Marcon","orcid":null,"position":8,"is_corresponding":false},{"id":277394,"name":"Fengling Li","orcid":"0000-0002-7962-9033","position":9,"is_corresponding":false},{"id":36715,"name":"Irene Chau","orcid":"0000-0002-2313-973X","position":10,"is_corresponding":false},{"id":36710,"name":"Albina Bolotokova","orcid":null,"position":11,"is_corresponding":false},{"id":323183,"name":"Qin Su","orcid":"0000-0001-9437-6292","position":12,"is_corresponding":false},{"id":634964,"name":"Ming Lei","orcid":"0000-0002-1153-4791","position":13,"is_corresponding":false},{"id":563498,"name":"Yanli Liu","orcid":"0000-0003-0197-7617","position":14,"is_corresponding":false},{"id":277392,"name":"Magdalena M. Szewczyk","orcid":"0000-0001-9243-1630","position":15,"is_corresponding":false},{"id":462754,"name":"Aiping Dong","orcid":null,"position":16,"is_corresponding":false},{"id":634965,"name":"Sina Kazemzadeh","orcid":"0000-0003-3472-7032","position":17,"is_corresponding":false},{"id":634966,"name":"Tigran M. Abramyan","orcid":"0000-0002-7224-6072","position":18,"is_corresponding":false},{"id":275706,"name":"Irina K Popova","orcid":"0009-0006-8612-3264","position":19,"is_corresponding":false},{"id":275705,"name":"Nathan W Hall","orcid":"0009-0008-5373-0070","position":20,"is_corresponding":false},{"id":275816,"name":"Matthew J. Meiners","orcid":"0009-0007-4020-4752","position":21,"is_corresponding":false},{"id":275817,"name":"Marcus A. Cheek","orcid":"0009-0005-9814-3097","position":22,"is_corresponding":false},{"id":36729,"name":"Elisa Gibson","orcid":"0000-0002-7112-337X","position":23,"is_corresponding":false},{"id":36749,"name":"Dmitri Kireev","orcid":"0000-0001-8479-8555","position":24,"is_corresponding":false},{"id":43252,"name":"Jack Greenblatt","orcid":"0000-0003-1762-2861","position":25,"is_corresponding":false},{"id":237417,"name":"Michael‐Christopher Keogh","orcid":"0000-0002-2219-8623","position":26,"is_corresponding":false},{"id":345478,"name":"Jinrong Min","orcid":"0000-0001-5210-3130","position":27,"is_corresponding":false},{"id":36712,"name":"Peter J. Brown","orcid":"0000-0002-8454-0367","position":28,"is_corresponding":false},{"id":277407,"name":"Masoud Vedadi","orcid":"0000-0002-0574-0169","position":29,"is_corresponding":false},{"id":84362,"name":"C.H. Arrowsmith","orcid":"0000-0002-4971-3250","position":30,"is_corresponding":false},{"id":277408,"name":"Dalia Baršytė-Lovejoy","orcid":"0000-0002-6560-9621","position":31,"is_corresponding":false},{"id":540831,"name":"Lindsey I. James","orcid":"0000-0002-6034-7116","position":32,"is_corresponding":false},{"id":36797,"name":"Matthieu Schapira","orcid":"0000-0002-1047-3309","position":33,"is_corresponding":false},{"id":277399,"name":"David Dilworth","orcid":"0000-0001-5557-9476","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:53:20.374789Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}