Lysine-specific demethylase 5 family (KDM5 family) (KDM5)

The Lysine-specific demethylase 5 (KDM5) family, also known as the JARID1 family, consists of four members (KDM5A, KDM5B, KDM5C, and KDM5D) that function as histone demethylases specifically targeting tri- and di-methylated lysine 4 on histone H3 (H3K4me3/2) [PMID: 28249148]. These enzymes utilize a Jumonji C (JmjC) domain to catalyze demethylation in an oxygen-, iron-, and alpha-ketoglutarate-dependent manner, playing a central role in regulating gene expression and chromatin architecture [PMID: 31434380]. KDM5 proteins are frequently overexpressed in various cancers, including breast, lung, and prostate cancers, where they contribute to tumor heterogeneity and the emergence of drug-tolerant persister cells that drive therapy resistance [PMID: 20305634]. Additionally, mutations in KDM5 family members, particularly KDM5C, are linked to X-linked intellectual disability and other neurodevelopmental disorders [PMID: 15688009]. Therapeutic development is currently focused on small-molecule inhibitors designed to block the JmjC domain, thereby restoring H3K4 methylation levels and sensitizing resistant tumors to standard-of-care treatments [PMID: 30104678].

Other names

JARID1 familyJumonji/ARID domain-containing protein 1 familyH3K4 demethylase familyRBP2 family

Competitive inhibition of the alpha-ketoglutarate binding site within the Jumonji C (JmjC) catalytic domain to prevent the demethylation of H3K4me3 and H3K4me2.