Ataxia telangiectasia: G(2) checkpoint and chromosomal damage in proliferating lymphocytes

There is a checkpoint pathway in eukaryotic cells that depends on ATM (atax ia telangiectasia mutated) kinase which activates the processes leading to the repair of DNA damage and also lengthens the G(2) stage of the cell cycl e. In cells from ataxia telangiectasia patients, due to their lack of activ e ATM kinase, an increase in chromosomal aberrations and a failure to induc e G(2) lengthening could be expected. However, the basal G(2) timing in ata xia telangiectasia cells was longer than in controls and was further extend ed after X-ray irradiation (0.4 Gy), although to a lesser extent than in co ntrols. Moreover, in control cells caffeine shortened G(2) and increased ch romosomal damage 7-fold, while in ataxia telangiectasia cells caffeine only trebled aberration yield without shortening G(2). As caffeine is an inhibi tor of ATM kinase, these results suggest the existence of some redundant AT M-independent checkpoint in G(2) of ataxia telangiectasia cells. The differ ential response to caffeine of ataxia telangiectasia and control lymphocyte s may be explained by the presence of two different subpathways in the G(2) checkpoint: one regulating the processing and repair of damaged DNA and th e other controlling G(2) timing. While in controls both subpathways may be mediated by ATM kinase, in ataxia telangiectasia cells caffeine-sensitive A TR kinase and the caffeine-insensitive DNA-PK kinases might be responsible for DNA repair and the G(2) delay subpathways, respectively. Confirmation o f this model in ataxia telangiectasia cells with another cell type in which both subpathways are mediated by DNA-PK should define whether a metylxanth ine such as caffeine may also have an additional direct inhibitory effect o n DNA repair.