The Feature of BRCA1 function on DNA Damage Repair within higher-order chromatin structure

2016 Fiscal Year Final Research Report

• Project/Area Number: 26460402
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: St. Marianna University School of Medicine
• Principal Investigator: Wu Wenwen 聖マリアンナ医科大学, 医学研究科, 講師 (10434408)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: BRCA1 / FANCJ / CtIP / HP1 / H3K9me2 / HKMTi / PARPi

Outline of Final Research Achievements

Stable retention of the BRCA1/BARD1 complex at sites of DNA damage is required for a proper response to DNA double-strand breaks. In this study, we found that the BRCT domain of BARD1 is also required for the retention of the complex at damaged sites through its interaction with HP1γ. In response to DNA damage, BARD1 interacts with Lys9-dimethylated histone H3 (H3K9me2) in an ATM-dependent manner. This interaction is mediated by HP1γ. A conserved HP1-binding motif in the BARD1 BRCT domain directly interacts with the chromoshadow domain of HP1γ; mutations in this motif disturb the retention of BRCA1/BARD1 at damaged loci. The histone lysine methyltransferase (HKMT) inhibitors abolish this retention and demonstrated synergetic inhibition of clonogenic cell growth with poly (ADP-ribose) polymerase (PARP) inhibitor olaparib.
FANCJ and CtIP localize at DSB sites through BARD1-HP1 interaction. In conclusion, HP1 regulats HR through retention of FANCJ and CtIP, mediated by BRCA1/BARD1.

Free Research Field

病態医化学