Nuclear receptor binding SET domain protein 2 (NSD2) PWWP1 domain (NSD2-PWWP1)

Nuclear receptor binding SET domain protein 2 (NSD2), also known as MMSET or WHSC1, is a histone lysine methyltransferase responsible for the global mono- and dimethylation of lysine 36 on histone H3 (H3K36) [4, 6]. The PWWP1 domain is a critical N-terminal reader module that recognizes H3K36me2 and H3K36me3 marks, anchoring the enzyme to chromatin to facilitate the propagation of epigenetic states [1, 13]. Dysregulation of NSD2, frequently occurring via the t(4;14) translocation in multiple myeloma or hyper-activating mutations like E1099K in pediatric acute lymphoblastic leukemia, leads to aberrant gene expression programs and accelerated cell proliferation [10, 16]. Pharmacological targeting of the NSD2-PWWP1 domain using selective antagonists such as the chemical probe UNC6934 disrupts its interaction with methylated nucleosomes [5, 17]. This antagonism induces the mislocalization of NSD2 to the nucleolus and inhibits its ability to drive oncogenic transcriptional profiles, offering a promising therapeutic strategy where catalytic SET domain inhibition has proven challenging [6, 8].

Other names

MMSET PWWP1 domainWHSC1 PWWP1 domainKMT3G PWWP1 domainWolf-Hirschhorn syndrome candidate 1 PWWP1Multiple myeloma SET domain PWWP1Histone-lysine N-methyltransferase NSD2 PWWP1 domain

Small-molecule antagonists bind to the conserved aromatic cage of the PWWP1 domain, competitively blocking its recognition of dimethylated H3K36 (H3K36me2) and nucleosomal DNA, which causes the NSD2 protein to disengage from chromatin and mislocalize to the nucleolus [5, 17].