Suppression and recovery of BRCA1-mediated transcription by HP1γ via modulation of promoter occupancy.
Heterochromatin protein 1γ (HP1γ) is a chromatin protein involved in gene silencing. Herein, we show that HP1γ 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 HP1γ mutants and small interfering RNAs for histone methyltransferases to show that BRCA1-HP1γ interaction, but not methylated histone binding, is important in HP1γ repression of BRCA1-mediated transcription. Time-lapse studies on promoter association and histone methylation after DNA damage revealed that HP1γ accumulates at the promoter before DNA damage, but BRCA1 is recruited at the promoter after the damage while promoter-resident HP1γ is disassembled. Importantly, HP1γ assembly recovers after release from the damage in a BRCA1-HP1γ interaction-dependent manner and targets SUV39H1. HP1γ/SUV39H1 restoration at the promoter results in BRCA1 disassembly and histone methylation, after which transcription repression resumes. We propose that through interaction with BRCA1, HP1γ 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.
Department of Molecular Science and Technology College of Natural Sciences Ajou University, Suwon, Korea.
Jae Duk
JD
Choi
Mi Ae
MA
Park
Jong-Soo
JS
Lee
D019313:BRCA1 Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002460:Cell Line; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D000097642:GADD45 Proteins
D019313:BRCA1 Protein; D002868:Chromosomal Proteins, Non-Histone; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D000097642:GADD45 Proteins; C518294:CBX3 protein, human