HP1β recruits RING1A to ubiquitinate histone H2A for BRCA1-mediated resection of double-stand breaks.

Efficient DNA double-strand break (DSB) repair by homologous recombination (HR), as initiated by BRCA1 recruitment orchestrated by histone and non-histone proteins, is critical to genome stability, replication, transcription, and cancer avoidance. Here we reveal Heterochromatin Protein1 beta (HP1β) promotes BRCA1 enrichment at DNA DSB sites in gene-rich regions, and this is impaired by HP1β depletion. We find that HP1β is specifically enriched at DSBs within gene-rich regions via its Chromo Shadow Domain (CSD) that interacts with both Chromatin Assembly Factor 1 and the RING1A ubiquitinase component of Polycomb Repressor Complex 1. The resulting protein complex facilitates BRCA1 recruitment by promoting H2A lysine 119 ubiquitination. Collective findings reveal a novel mechanism whereby HP1β interactions, mediated through its CSD of HP1β interaction with RING1A, promotes H2AK119 ubiquitination to facilitate BRCA1 recruitment and orchestrate efficient HR and CtIP-dependent DNA resection at DSB sites in gene-rich active chromatin.