Novel function of ATM for genome maintenance: Regulation of cell cycle factors without chromosomal damage

2014 Fiscal Year Final Research Report

• Project/Area Number: 24650622
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: Kyushu University
• Principal Investigator: FUJITA Masatoshi 九州大学, 薬学研究科(研究院), 教授 (30270713)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: ATM / Cdt1 / SNF2H / 細胞周期 / クロマチン

Outline of Final Research Achievements

Ataxia-telangiectasia mutated (ATM) plays crucial roles in DNA damage responses, especially with regard to DNA double-strand breaks (DSBs). Here, we found that ATM is involved in timely degradation of Cdt1, a critical replication licensing factor, during the unperturbed S phase. The novel ATM function for Cdt1 regulation was dependent on its kinase activity and NBS1. Indeed, we found that ATM is moderately phosphorylated at Ser1981 during the S phase. ATM silencing induced partial reduction in levels of Skp2, a component of SCFSkp2 ubiquitin ligase that controls Cdt1 degradation. Furthermore, Skp2 silencing resulted in Cdt1 stabilization like ATM inhibition. In addition, Akt inhibition led to modest stabilization of Cdt1. Therefore, the ATM-Akt-SCFSkp2 pathway may partly contribute to the novel ATM function. Finally, ATM inhibition rendered cells hypersensitive to induction of re-replication, indicating importance for maintenance of genome stability.

Free Research Field

分子生物学／分子腫瘍学