Suppression and recovery of BRCA1-mediated transcription by HP1γ via modulation of promoter occupancy

Heterochromatin protein 1 gamma (HP1 gamma) is a chromatin protein involved in gene silencing. Herein, we show that HP1 gamma interacts with breast cancer type 1 susceptibility protein (BRCA1) and regulates BRCA1-mediated transcription via modulation of promoter occupancy and histone modification. We used several HP1 gamma mutants and small interfering RNAs for histone methyltransferases to show that BRCA1-HP1 gamma interaction, but not methylated histone binding, is important in HP1 gamma repression of BRCA1-mediated transcription. Time-lapse studies on promoter association and histone methylation after DNA damage revealed that HP1 gamma accumulates at the promoter before DNA damage, but BRCA1 is recruited at the promoter after the damage while promoter-resident HP1 gamma is disassembled. Importantly, HP1 gamma assembly recovers after release from the damage in a BRCA1-HP1 gamma interaction-dependent manner and targets SUV39H1. HP1 gamma/SUV39H1 restoration at the promoter results in BRCA1 disassembly and histone methylation, after which transcription repression resumes. We propose that through interaction with BRCA1, HP1 gamma is guided to the BRCA1 target promoter during recovery and functions in the activation-repression switch and recovery from BRCA1-mediated transcription in response to DNA damage.