BRCA1-Ku80 protein interaction enhances end-joining fidelity of chromosomal double-strand breaks in the G1 phase of the cell cycle.
Quality control of DNA double-strand break (DSB) repair is vital in preventing mutagenesis. Non-homologous end-joining (NHEJ), a repair process predominant in the G1 phase of the cell cycle, rejoins DSBs either accurately or with errors, but the mechanisms controlling its fidelity are poorly understood. Here we show that BRCA1, a tumor suppressor, enhances the fidelity of NHEJ-mediated DSB repair and prevents mutagenic deletional end-joining through interaction with canonical NHEJ machinery during G1. BRCA1 binds and stabilizes Ku80 at DSBs through its N-terminal region, promotes precise DSB rejoining, and increases cellular resistance to radiation-induced DNA damage in a G1 phase-specific manner. These results suggest that BRCA1, as a central player in genome integrity maintenance, ensures high fidelity repair of DSBs by not only promoting homologous recombination repair in G2/M phase but also facilitating fidelity of Ku80-dependent NHEJ repair, thus preventing deletional end-joining of chromosomal DSBs during G1.
Department of Radiation Oncology, The Ohio State University Medical Center, Arthur G. James Comprehensive Cancer Center, Columbus, OH 43210, USA.
Guochun
G
Jiang
Isabelle
I
Plo
Tong
T
Wang
Mohammad
M
Rahman
Ju Hwan
JH
Cho
Eddy
E
Yang
Bernard S
BS
Lopez
Fen
F
Xia
D034961:Antigens, Nuclear / Q000378:metabolism*; D019313:BRCA1 Protein / Q000378:metabolism*; D002453:Cell Cycle; D047369:Chromatin Immunoprecipitation; D004247:DNA / Q000032:analysis; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016193:G1 Phase; D017353:Gene Deletion; D005982:Glutathione Transferase / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D000072200:Ku Autoantigen; D016296:Mutagenesis; D009687:Nuclear Proteins / Q000378:metabolism; D011485:Protein Binding; D011995:Recombination, Genetic; D015398:Signal Transduction
D034961:Antigens, Nuclear; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D004247:DNA; D005982:Glutathione Transferase; C000606509:Xrcc6 protein, human; D000072200:Ku Autoantigen