Defective control of apoptosis and mitotic spindle checkpoint in heterozygous carriers of ATM mutations

Ataxia telangiectasia (AT) carrier-derived :lymphoblastoid cell lines (AT-L CLs/hetero) with suboptimal ATM protein expression were examined for the re gulation of radiosensitivity, apoptosis, and mitotic spindle checkpoint in response to DNA-damaging agents. Although AT-LCLs/hetero showed intermediat e radiation sensitivity, as determined by clonogenic assay, they were resis tant to early-onset apoptosis, as much as AT patient-derived LCLs (AT-LCLs/ homo) Furthermore, two of three AT-LCLs/hetero shelved defective mitotic sp indle checkpoint control in response to X-ray irradiation, which is, a rece ntly characterized biological feature in AT-LCLs/homo, Our findings indicat e that carriers of ATM mutation have biological abnormalities due to haploi nsufficiency of ATM protein or dominant-negative effect of mutant ATM prote in. Thus, although it is still controversial whether ATM mutation carriers are at higher risk for cancer during adulthood, our findings based on in vi tro biological indicators support the notion that at least some of such car riers are at a higher risk for cancer development than those without ATM mu tation. Oar findings may help to reevaluate epidemiological studies on canc er susceptibility in AT carriers.