| Budget Amount *help |
¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000)
Fiscal Year 2018: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2017: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2016: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
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| Outline of Final Research Achievements |
The aim of this study is to characterize the DNA damages induced by estrogen and clarify the molecular mechanism of how estrogen-induced DNA damages are repaired. To this end, we generated BRCA1 and TOP2b deficient cells using breast cancer MCF-7 cells. We found that estrogen induced Top2b; covalently bound to DSB ends, named TOP2cc, in serum starved G1-phase cells. The loss of BRCA1 caused the accumulation of TOP2cc induced by estrogen, indicating an important role of BRCA1 in the repair of estrogen-induced DSBs. We have previously demonstrated that MRE11 nuclease also functions in the removal of Top2cc from DSB ends. BRCA1 promotes the recruitment of MRE11 onto Top2cc sites for subsequent removal of Top2cc. Our results suggest the loss of BRCA1 enhances estrogen’s genotoxicity. This function of BRCA1 may help explain the female organ-specific carcinogenesis of BRCA1-mutation carriers.
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