title: Deregulation of Cdt1 induces chromosomal damage without rereplication and leads to chromosomal instability.
abstract: The activity of human Cdt1 is negatively regulated by multiple mechanisms. This suggests that Cdt1 deregulation may have a deleterious effect. Indeed, it has been suggested that overexpression of Cdt1 can induce rereplication in cancer cells and that rereplication activates Ataxia-telangiectasia-mutated (ATM) kinase and/or ATM- and Rad3-related (ATR) kinase-dependent checkpoint pathways. In this report, we highlight a new and interesting aspect of Cdt1 deregulation: data from several different systems all strongly indicate that unregulated Cdt1 overexpression at pathophysiological levels can induce chromosomal damage other than rereplication in non-transformed cells. The most important finding in these studies is that deregulated Cdt1 induces chromosomal damage and activation of the ATM-Chk2 DNA damage checkpoint pathway even in quiescent cells. These Cdt1 activities are negatively regulated by cyclin A/Cdks, probably through modification by phosphorylation. Furthermore, we found that deregulated Cdt1 induces chromosomal instability in normal human cells. Since Cdt1 is overexpressed in cancer cells, this would be a new molecular mechanism leading to carcinogenesis.
authors.affiliation: Virology Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuohku, Tokyo 104-0045, Japan.
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Tatsumi
authors.forename: Nozomi
authors.initials: N
authors.lastname: Sugimoto
authors.forename: Takashi
authors.initials: T
authors.lastname: Yugawa
authors.forename: Mako
authors.initials: M
authors.lastname: Narisawa-Saito
authors.forename: Tohru
authors.initials: T
authors.lastname: Kiyono
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Fujita
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2; D043171:Chromosomal Instability; D002875:Chromosomes; D004249:DNA Damage; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007621:Karyotyping; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D051738:Origin Recognition Complex / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C103706:CDC6 protein, human; C467199:CDT1 protein, human; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D051738:Origin Recognition Complex; D025521:Tumor Suppressor Proteins; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; C578632:Chek2 protein, rat; D017346:Protein Serine-Threonine Kinases