BMI-1 regulates DNA end resection and homologous recombination repair
Amira Fitieh,
Andrew J. Locke,
Fatemeh Mashayekhi,
Fajr Khaliqdina,
Ajit K. Sharma,
Ismail Hassan Ismail
Affiliations
Amira Fitieh
Biophysics Department, Faculty of Science, Cairo University, 12613 Giza, Egypt; Department of Oncology, Faculty of Medicine & Dentistry, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada
Andrew J. Locke
Department of Oncology, Faculty of Medicine & Dentistry, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada
Fatemeh Mashayekhi
Department of Oncology, Faculty of Medicine & Dentistry, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada
Fajr Khaliqdina
Department of Oncology, Faculty of Medicine & Dentistry, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada
Ajit K. Sharma
Department of Oncology, Faculty of Medicine & Dentistry, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada
Ismail Hassan Ismail
Biophysics Department, Faculty of Science, Cairo University, 12613 Giza, Egypt; Department of Oncology, Faculty of Medicine & Dentistry, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB T6G 1Z2, Canada; Corresponding author
Summary: BMI-1 is an essential regulator of transcriptional silencing during development. Recently, the role of BMI-1 in the DNA damage response has gained much attention, but the exact mechanism of how BMI-1 participates in the process is unclear. Here, we establish a role for BMI-1 in the repair of DNA double-strand breaks by homologous recombination (HR), where it promotes DNA end resection. Mechanistically, BMI-1 mediates DNA end resection by facilitating the recruitment of CtIP, thus allowing RPA and RAD51 accumulation at DNA damage sites. Interestingly, treatment with transcription inhibitors rescues the DNA end resection defects of BMI-1-depleted cells, suggesting BMI-1-dependent transcriptional silencing mediates DNA end resection. Moreover, we find that H2A ubiquitylation at K119 (H2AK119ub) promotes end resection. Taken together, our results identify BMI-1-mediated transcriptional silencing and promotion of H2AK119ub deposition as essential regulators of DNA end resection and thus the progression of HR.
