BMI1/RING1A and BMI1/RNF2 are E3 ubiquitin ligase complexes that mediate the monoubiquitination of histone 2A (H2A). This is an essential function of polycomb repressive complex 1 (PRC1). PRT4165 is an inhibitor of the ubiquitin ligase activity of PRC1. It blocks BMI1/RING1A self-ubiquitination (IC50 = 3.9 μM), as well as polyubiquitination of topoisomerase 2α in cells. PRT4165 inhibits ubiquitination of H2A by either RNF2 or RING1. Through these actions, PRT4165 prevents the accumulation of detectable ubiquitin at DNA double-strand breaks, the retention of response proteins around breaks, and the repair of breaks.
