KDM5

KDM5 refers to a family of histone lysine demethylases that selectively remove di- and tri-methyl groups from lysine 4 on histone H3 (H3K4me2/3). By erasing activating transcription marks, KDM5 enzymes generally repress gene expression and influence chromatin structure. The mammalian family comprises four paralogs: KDM5A (RBP2), KDM5B (PLU-1), KDM5C (SMCX), and KDM5D (SMCY). KDM5D is Y-linked; the others are autosomal or X-linked and broadly expressed.

All KDM5 proteins contain a JmjC catalytic domain that requires ferrous iron and α-ketoglutarate to hydroxylate the methyl group, producing formaldehyde and succinate. Demethylation typically proceeds in steps from me3 to me2 to me1 to me0, lowering H3K4 methylation levels and altering transcriptional potential.

Domain architecture varies, but members commonly include a JmjN–JmjC catalytic core and regulatory modules such as ARID DNA-binding domains and PHD fingers that recognize histone marks. These domains help recruit KDM5 enzymes to promoters and modulate substrate specificity and interactions with co-regulators.

Biologically, KDM5 proteins regulate cell cycle–related genes, differentiation, and genome integrity. They participate in stem cell maintenance and DNA damage responses. Mutations or misregulation are linked to developmental disorders and cancer; for example, KDM5C mutations are associated with X-linked intellectual disability, and altered KDM5A/B activity is observed in several tumors.

Therapeutically, KDM5 demethylases are targets of ongoing drug discovery. Several small-molecule inhibitors with varying selectivity have been described, showing preclinical antiproliferative effects in models driven by dysregulated H3K4 methylation. Continued research aims to define context-specific roles and develop clinically useful compounds.