Read–write mechanisms of H2A ubiquitination by Polycomb repressive complex 1

Victoria Godínez López, Marco Igor Valencia-Sánchez, Stephen Abini-Agbomson, Jonathan F. Thomas, Rachel Lee, Pablo Ioannes, Brian A. Sosa, Jean-Paul Armache and Karim-Jean Armache ()
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Victoria Godínez López: New York University Grossman School of Medicine
Marco Igor Valencia-Sánchez: New York University Grossman School of Medicine
Stephen Abini-Agbomson: New York University Grossman School of Medicine
Jonathan F. Thomas: New York University Grossman School of Medicine
Rachel Lee: New York University Grossman School of Medicine
Pablo Ioannes: New York University Grossman School of Medicine
Brian A. Sosa: New York University Grossman School of Medicine
Jean-Paul Armache: Pennsylvania State University
Karim-Jean Armache: New York University Grossman School of Medicine

Nature, 2024, vol. 636, issue 8043, 755-761

Abstract: Abstract Epigenetic inheritance of silent chromatin domains is fundamental to cellular memory during embryogenesis, but it must overcome the dilution of repressive histone modifications during DNA replication1. One such modification, histone H2A lysine 119 monoubiquitination (H2AK119Ub), needs to be re-established by the Polycomb repressive complex 1 (PRC1) E3 ligase to restore the silent Polycomb domain2,3. However, the exact mechanism behind this restoration remains unknown. Here, combining cryo-electron microscopy (cryo-EM) and functional approaches, we characterize the read–write mechanism of the non-canonical PRC1-containing RYBP (ncPRC1RYBP). This mechanism, which functions as a positive-feedback loop in epigenetic regulation4,5, emphasizes the pivotal role of ncPRC1RYBP in restoring H2AK119Ub. We observe an asymmetrical binding of ncPRC1RYBP to H2AK119Ub nucleosomes, guided in part by the N-terminal zinc-finger domain of RYBP binding to residual H2AK119Ub on nascent chromatin. This recognition positions the RING domains of RING1B and BMI1 on the unmodified nucleosome side, enabling recruitment of the E2 enzyme to ubiquitinate H2AK119 within the same nucleosome (intra-nucleosome read–write) or across nucleosomes (inter-nucleosome read–write). Collectively, our findings provide key structural and mechanistic insights into the dynamic interplay of epigenetic regulation, highlighting the significance of ncPRC1RYBP in H2AK119Ub restoration to sustain repressive chromatin domains.

Date: 2024
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DOI: 10.1038/s41586-024-08183-5

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