A role of ATR-CDC6 pathway for the maintenance of genome integrity in response to endogenous stress during DNA replication

Research Project

Project/Area Number	15K18478
Research Category	Grant-in-Aid for Young Scientists (B)
Allocation Type	Multi-year Fund
Research Field	Molecular biology
Research Institution	Kyushu University
Principal Investigator	Yoshida Kazumasa 九州大学, 薬学研究院, 助教 (80715392)
Project Period (FY)	2015-04-01 – 2017-03-31
Project Status	Completed (Fiscal Year 2016)
Budget Amount *help	¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000) Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000) Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywords	DNA複製 / 複製ストレス / ATR / 染色体 / DNA損傷応答 / ゲノム安定性 / 細胞周期 / 複製チェックポイント / 複製フォーク / クロマチン結合
Outline of Final Research Achievements	ATR is a checkpoint kinase responding to DNA replication stress and essential for cell survival. This study aimed to reveal how ATR is activated in response to the endogenous replication stress and how CDC6 functions in such process. We analyzed the chromatin binding kinetics of human ATR and its co-factors in the presence and absence of exogenous replication stress. In addition, we have established an experimental model system that recapitulates replication fork arrest using an artificial DNA-protein tethering on the chromatin. This model system is useful for the analysis of stress response mechanism(s) at stalled forks and would provide a further understanding of cancer and genetic diseases characterized by genomic instability. Further development in therapy of such diseases would also be anticipated.