Structural basis of the histone ubiquitination read-write mechanism of RYBP-PRC1

Histone H2A monoubiquitination (H2Aub1) by the PRC1 subunit RING1B entails a positive feedback loop, mediated by the RING1B-interacting protein RYBP. We uncover that human RYBP-PRC1 binds unmodified nucleosomes via RING1B but H2Aub1-modified nucleosomes via RYBP. RYBP interactions with both ubiquitin and the nucleosome acidic patch create the high binding affinity that favors RYBP- over RING1B-directed PRC1 binding to H2Aub1-modified nucleosomes; this enables RING1B to monoubiquitinate H2A in neighboring unmodified nucleosomes. Cryo-EM studies reveal that RYBP-PRC1 uses two distinct interfaces for binding unmodified and H2Aub1-modified nucleosomes. These binding modes enable the complex to generate H2Aub1 chromatin domains by a read-write mechanism.