Analogue-Sensitive Inhibition of Histone Demethylases Uncovers Member-Specific Function in Ribosomal Protein Synthesis.

ABSTRACT: Lysine demethylases (KDMs) catalyze the oxidative removal of the methyl group from histones using earth-abundant iron and the metabolite 2-oxoglutarate (2OG). KDMs have emerged as master regulators of eukaryotic gene expression and are novel drug targets; small-molecule inhibitors of KDMs are in the clinical pipeline for the treatment of human cancer. Yet, mechanistic insights into the functional heterogeneity of human KDMs are limited, necessitating the development of chemical probes for precision targeting. Herein, we identify analogue-sensitive (as) mutants of the KDM4 subfamily to elucidate member-specific biological functions in a temporally defined manner. By replacing the highly conserved phenylalanine residue in the active site of KDM4 members with alanine, we develop mutant

SUBMITTER: Kuwik J 

PROVIDER: S-EPMC11783601 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature