ATM regulates Cdt1 stability during the unperturbed S phase to prevent re-replication

Satoko Iwahori, Daisuke Kohmon, Junya Kobayashi, Yuhei Tani, Takashi Yugawa, Kenshi Komatsu, Tohru Kiyono, Nozomi Sugimoto, Masatoshi Fujita

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Abstract

Ataxia-telangiectasia mutated (ATM) plays crucial roles in DNA damage responses, especially with regard to DNA double-strand breaks (DSBs). However, it appears that ATM can be activated not only by DSB, but also by some changes in chromatin architecture, suggesting potential ATM function in cell cycle control. Here, we found that ATM is involved in timely degradation of Cdt1, a critical replication licensing factor, during the unperturbed S phase. At least in certain cell types, degradation of p27Kip1 was also impaired by ATM inhibition. 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, as reported previously, ATM silencing partially prevented Akt phosphorylation at Ser473, indicative of its activation, and 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.

Original languageEnglish
Pages (from-to)471-481
Number of pages11
JournalCell Cycle
Volume13
Issue number3
DOIs
Publication statusPublished - Feb 1 2014

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All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

Iwahori, S., Kohmon, D., Kobayashi, J., Tani, Y., Yugawa, T., Komatsu, K., ... Fujita, M. (2014). ATM regulates Cdt1 stability during the unperturbed S phase to prevent re-replication. Cell Cycle, 13(3), 471-481. https://doi.org/10.4161/cc.27274