The activity of human Cdtl is negatively regulated by multiple mechanisms. This suggests that Cdtl 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 Ata3da-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 Cdtl 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 Cdtl 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 Cdtl induces chromosomal instability in normal human cells. Since Cdt1 is overexpressed in cancer cells, this would be a new molecular mechanism leading to carcinogenesis.
All Science Journal Classification (ASJC) codes
- Cell Biology