Histone-lysine N-methyltransferase NSD2 (NSD2)

Histone-lysine N-methyltransferase NSD2 is an epigenetic enzyme that catalyzes the mono- and dimethylation of lysine 36 on histone H3 (H3K36me1/2). This activity modifies chromatin, regulates gene expression, and is integral to processes such as transcription and DNA repair. NSD2 is ubiquitously expressed and encoded by the NSD2 (WHSC1) gene on chromosome 4; it is also known by the aliases MMSET and RE-IIBP. Pathogenic alterations in NSD2, such as overexpression, gene fusion (notably t(4;14)), and oncogenic mutations, are implicated in various cancers, and its loss contributes to developmental disorders like Wolf-Hirschhorn syndrome. Structurally, NSD2 contains several domains typical for histone methyltransferases, including SET, PWWP, PHD zinc fingers, HMG box, and C5HCH motif, enabling chromatin binding and catalytic activity. No clinically approved drugs selectively inhibit NSD2, but experimental compounds such as MRT10241866a are under investigation. NSD2 is considered a critical therapeutic target in oncology and epigenetics, but targeting challenges stem from its diverse roles in normal development and essential genomic functions.

Other names

MMSETWHSC1RE-IIBPTRX5KIAA1090

Inhibition of histone H3K36 methylation, leading to altered gene transcription and chromatin state; Disruption of NSD2 PWWP domain interaction with methylated histone tails; Potential modulation or suppression of NSD2 catalytic SET domain activity