Cryo-EM structure, enzymatic activity and genome targeting of canonical PRC1

Canonical Polycomb repressive complex 1 (cPRC1) preserves cell fate decisions by repressing aberrant transcription of developmental regulator genes. We report the cryo-electron microscopy structure of the human cPRC1 holocomplex assembled from RING1B, BMI1, PHC2 and CBX7 bound to an H3K27me3-modified mononucleosome together with the ubiquitin-conjugating enzyme UBCH5C. cPRC1 adopts a compact, highly integrated architecture in which the subunits RING1B, BMI1 and PHC2 form an extended interface that positions UBCH5C on the nucleosome to enable efficient monoubiquitination of histone H2A at K119. This organization is conserved in Drosophila, where mutational analyses identify the PHC2 ortholog Polyhomeotic (Ph) as a central scaffold and targeting factor. The Ph HD domain is required for complex assembly, whereas the Ph SAM domain is dispensable for assembly but essential for cPRC1 recruitment to Polycomb target genes and productive H2A monoubiquitination at these loci.