Functional analysis of BRCA1 as the molecular basis of breast cancer therapy

2017 Fiscal Year Final Research Report

• Project/Area Number: 26290042
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: St. Marianna University School of Medicine
• Principal Investigator: OHTA Tomohiko 聖マリアンナ医科大学, 医学研究科, 教授 (60233136)
• Co-Investigator(Kenkyū-buntansha): 朴 成和 国立研究開発法人国立がん研究センター, 中央病院, 科長 (50505948)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Keywords: 乳癌 / 治療 / BRCA1 / BARD1 / DNA損傷

Outline of Final Research Achievements

In this study, we found that BARD1 interacts with Lys9-dimethylated histone H3 (H3K9me2) after DNA damage in an ATM-dependent but RNF168-independent manner. This interaction is mediated by HP1-gamma. A conserved HP1-binding motif in the BARD1 BRCT domain directly interacts with the chromoshadow domain of HP1 in vitro; mutations in this motif disrupt the retention of BRCA1/BARD1 at DNA double-strand break (DSB) sites. The inhibition of BARD1-HP1 interaction also inhibits accumulation of CtIP, FANCJ and RAD51 at DSB sites, suppressed damage-induced sister chromatid exchange, and allow ectopic accumulation of RIF1, an effector of non-homologous end joining, at the damaged loci in S-phase. The results indicate that the BARD1-HP1 interaction is critical to mediate homologous recombination repair of DSB.

Free Research Field

応用分子腫瘍学