Abstract
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.
Highlights
Quality control of DNA double-strand break repair is poorly understood
BRCA1 binds and stabilizes Ku80 at double-strand break (DSB) 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 promoting homologous recombination repair in G2/M phase and facilitating fidelity of Ku80-dependent Non-homologous end-joining (NHEJ) repair, preventing deletional end-joining of chromosomal DSBs during G1
To investigate whether BRCA1 is implicated in NHEJ repair at the chromosomal level in mammalian cells, we stably introduced a NHEJ substrate in which the two I-SceI sites are separated by ϳ2 kb of intervening sequence (Fig. 1A), into human SV40-transformed fibroblast cells (GM639) [10]
Summary
Quality control of DNA double-strand break repair is poorly understood. Results: BRCA1 enhances the fidelity of NHEJ repair and prevents mutagenic deletional end-joining through interaction with canonical NHEJ machinery during G1. 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 promoting homologous recombination repair in G2/M phase and facilitating fidelity of Ku80-dependent NHEJ repair, preventing deletional end-joining of chromosomal DSBs during G1. We sought to investigate whether BRCA1, as a tumor suppressor, promotes fidelity of end-joining of DSBs through interaction with the C-NHEJ machinery, a function different from its known role in HR.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
