HGM2002 Poster Abstracts: 8. Disease Mechanisms
POSTER NO: 464
Tumor suppressor Chk2 is phosphorylated and activated at the sites of DNA breaks
Irene Ward, Xianglin Wu, Junjie Chen
The integrity of the DNA damage response pathway is essential for the prevention of neoplastic transformation. Several proteins involved in this pathway, including p53, BRCA1 and ATM, are frequently mutated in human cancer. Chk2 is a protein kinase that becomes rapidly phosphorylated and activated by ATM following DNA damage. Recently, heterozygous germ-line mutations in Chk2 have been identified in a subset of patients with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype, suggesting that Chk2 is a tumor suppressor gene. We reported earlier that two of the Chk2 mutations identified in Li-Fraumeni syndrome resulted in loss of Chk2 kinase activity. While one mutation within Chk2 forkhead homology-associated (FHA) domain, R145W, retains some basal kinase activity, this mutant cannot be phosphorylated at Thr-68, an ATM-dependent phosphorylation site, and cannot be activated following gamma radiation. Given the physiological impact of the DNA damage pathway in genome stability and cancer prevention, it is necessary to gain a better understanding of the regulation of Chk2 activation. Here we show that the T68-phosphorylated form of Chk2 forms distinct nuclear foci in response to ionizing radiation. Only this activated form localizes at sites of DNA strand breaks. The kinase activity of Chk2 and the number of Chk2 foci formed depend on the severity of DNA damage, and gradually decrease with time, corresponding with the reported time course of DNA repair. These results suggest that Chk2 activity is initiated and regulated at the sites of DNA strand breaks in response to ionizing radiation.
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