Abstract
Following DNA damage induced by ionizing radiation, cellular mechanisms, including cell-cycle checkpoint and DNA repair, play crucial roles in maintaining genomic stability. It has been shown that upon DNA damage the nuclear checkpoint kinases Chk1 and Chk2 are phosphorylated and activated by ATM kinase, and mediate cell-cycle checkpoint arrest. However, the mechanisms underlying recovery from DNA damage-induced cell-cycle checkpoint arrest remain largely unknown. Recently, we found that the nuclear Wip1 phosphatase, induced by p53 following DNA damage, associates with Chk1 and Chk2, and dephosphorylates (inactivates) phosphorylated-Chk1 and -Chk2 kinases, thereby mediating recovery from cell-cycle checkpoint arrest. Furthermore, we have shown that Wip1 dephosphorylates phosphorylated (activated) ATM kinase, thereby inhibiting its kinase activity. In my talk, I will overview our current model of on/ off regulation of cell-cycle checkpoint mechanism, and discuss about a possible coupling of cell-cycle checkpoint regulation with DNA repair. Since ATM, Chk2 kinases and Wip1 phosphatase have been considered as anti-oncogenic and oncogenic proteins, respectively, I will also refer to possible relationships between abnormal expression and/or function of these proteins and malignant tumors.
