ATR functional analysis using in vitro DNA replication system

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K12602
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Risk sciences of radiation and chemicals
• Research Institution: National Cancer Center Japan
• Principal Investigator: Shiotani Bunsyo 国立研究開発法人国立がん研究センター, 研究所, 主任研究員 (10627665)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: DNA複製 / DNA複製ストレス / ATR

Outline of Final Research Achievements

This study aimed to elucidate the role of ATR kinase that is essential for DNA replication. Analysis of phosphorylation factors in response to DNA replication in human normal epithelial cells and oncogene-induced DNA replication stress revealed remarkable ATR inhibitor sensitivity in approximately 200 types of phosphorylation factors. The pathway analysis of these factors suggested the possibility of RhoA pathway involved in cytoskeleton regulation as well as chromatin remodeling factor regulation in addition to conventional DNA damage response. These results suggest that ATR in the endogenous DNA replication stress response stably maintains the chromosome and maintains the survival of normal cells by phosphorylating different substrate groups from the DNA damage response caused by external factors.

Free Research Field

細胞分子生物学

Academic Significance and Societal Importance of the Research Achievements

本研究において、内因性DNA複製およびDNA複製ストレスに応答するATR基質群が同定されたことにより、外因性DNA損傷応答時とは異なる機構により染色体を安定に維持し正常細胞の生存を維持する機能が示唆された。このことはDNA複製にともなう複製エラー（突然変異）によるゲノム不安定性誘発・発がん過程におけるATRの機能解明が進み、これを応用しATR阻害療法が新たながん治療として開発が進むことが期待される。