title: ATM regulates Cdt1 stability during the unperturbed S phase to prevent re-replication.
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 p27(Kip1) 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 SCF(Skp2) 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-SCF(Skp2) 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.
authors.affiliation: Virology Division; National Cancer Center Research Institute; Chuohku, Tokyo, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Iwahori
authors.affiliation: Department of Cellular Biochemistry; Graduate School of Pharmaceutical Sciences; Kyushu University; Higashiku, Fukuoka, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kohmon
authors.affiliation: Radiation Biology Center; Kyoto University; Sakyo-ku, Kyoto, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Kobayashi
authors.affiliation: Department of Cellular Biochemistry; Graduate School of Pharmaceutical Sciences; Kyushu University; Higashiku, Fukuoka, Japan.
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Tani
authors.affiliation: Virology Division; National Cancer Center Research Institute; Chuohku, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yugawa
authors.affiliation: Radiation Biology Center; Kyoto University; Sakyo-ku, Kyoto, Japan.
authors.forename: Kenshi
authors.initials: K
authors.lastname: Komatsu
authors.affiliation: Virology Division; National Cancer Center Research Institute; Chuohku, Tokyo, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Kiyono
authors.affiliation: Department of Cellular Biochemistry; Graduate School of Pharmaceutical Sciences; Kyushu University; Higashiku, Fukuoka, Japan.
authors.forename: Nozomi
authors.initials: N
authors.lastname: Sugimoto
authors.affiliation: Department of Cellular Biochemistry; Graduate School of Pharmaceutical Sciences; Kyushu University; Higashiku, Fukuoka, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Fujita
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004247:DNA / Q000378:metabolism*; D004261:DNA Replication; D020868:Gene Silencing; D042822:Genomic Instability; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D059748:Proteolysis; D016196:S Phase; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C467199:CDT1 protein, human; D018797:Cell Cycle Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins; D044786:S-Phase Kinase-Associated Proteins; D004247:DNA; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: ATM; Akt-SCFSkp2; Cdt1; DNA damage and repair mechanisms; control of cell cycle progression