DEFECTIVE CONTROL OF APOPTOSIS, RADIOSENSITIVITY, AND SPINDLE CHECKPOINT IN ATAXIA-TELANGIECTASIA

We examined the regulation of apoptosis, radiosensitivity, and spindle checkpoint in response to DNA-damaging agents in ataxia telangiectasi a (AT)-derived lymphoblastoid cell lines (AT-LCLs), which lack AT muta ted (ATM) protein expression. In addition to the previous findings tha t AT-LCLs are defective in regulation of cell cycle at the G(1), S, an d G(2)-M checkpoints in response to X-ray irradiation (X-IR) and are h ighly sensitive to X-IR (J. Biol. Chem., 271: 20486-20493, 1996), we s howed for the first time that AT-LCLs were defective in X-IR-associate d spindle checkpoint control. The cells were also resistant to early a poptosis as much as LCLs derived from patients with Li-Fraumeni syndro me (LFS-LCLs). Terminal deoxynucleotidyl transferase-mediated nick end labeling assay of LCLs, however, demonstrated a significant increase in apoptotic cells among AT-LCLs cultured over a longer period after X -IR. These findings were in contrast to those of LFS-LCL, which showed very little increase in terminal deoxynucleotidyl transferase-mediate d nick end labeling-positive population, even in cells with hyperploid y. Thus, although early apoptosis and cell cycle controls in response to DNA damage are disrupted in broth ATM and p53 mutations, cells from AT patients are much more susceptible to late-onset apoptosis than th ose of LFS. These differences may depend on the level of accumulation of DNA damage and/or threshold that triggers late-onset cell death in ATM or p53 mutations. Our findings allow a better understanding of the role of ATM in p53-dependent and independent signal transduction path ways in response to DNA damaging agents.