PARENT SESSION
3:45 PM to 5:15 PM
Monday, April 22, 2002
Mini-Symposium 8
DNA Repair
Room: Nevada 6-7
, Co-Chair: Kao, Gary1; Glazer, Peter21University of Pennsylvania, Philadelphia, PA2Yale University, New Haven, CT
(MS08-6) Ku affects the ATM-dependent S-phase checkpoint response following ionizing radiation.
Wang, Xiang*,1, Zhou, Xiang-Yang1, Hu, Baocheng1, Chen, David2, Li, Gloria3, Iliakis, George4, Wang, Ya1, 1 Department of Radiation Oncology, Kimmel Cancer Center of Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA2 Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, CA3 Departments of Radiation Oncology and Medical Physics, Memorial Sloan-Kettering Cancer Center, New York, NY4 Institute of Medical Radiation Biology, University of Essen Medical School, Essen, Germany
ABSTRACT-
Following exposure to genotoxic stress, proliferating cells actively slow down the DNA replication through an S phase checkpoint to provide time for repair. The ATM-dependent pathway plays an important role in the S phase checkpoint response following ionizing irradiation (IR). We report a stronger S phase checkpoint response in irradiated Ku80-/- cells as compared with their wild-type counterparts, or DNA-PK-/- cells. At the same time, ATM kinase activity is higher in Ku80-/- cells than in Ku80+/+ cells. Wortmannin, a nonspecific inhibitor of ATM, not only reduces the activity of ATM kinase in Ku80-/- cells, but it also abolishes the stronger S phase checkpoint response. In addition, a specific ATM antisense oligonucleotide abolishes the stronger S checkpoint response in Ku80-/- cells. These results in aggregate indicate that the stronger S checkpoint in irradiated Ku80-/- cells is due to the higher ATM kinase activity. Ku80 is a DNA double strand binding protein and is essential for non-homologous end rejoining (NHEJ). As a result, there are more unrepaired DNA double strand breaks in Ku80-/- cell than in Ku80+/+ cells following IR, which might result in the observed stronger activation of ATM. We hypothesize that the function of the S phase checkpoint is to specifically facilitate homologous recombination repair (HRR) without affecting NHEJ.
KEYWORDS: Ku80, ATM, S-phase checkpoint, DNA damage