There is a checkpoint pathway in eukaryotic cells that depends on ATM (
ataxia telangiectasia mutated)
kinase which activates the processes leading to the repair of DNA damage and also lengthens the G(2) stage of the cell cycle. In cells from
ataxia telangiectasia patients, due to their lack of active ATM
kinase, an increase in
chromosomal aberrations and a failure to induce G(2) lengthening could be expected. However, the basal G(2) timing in
ataxia telangiectasia cells was longer than in controls and was further extended after X-ray irradiation (0.4 Gy), although to a lesser extent than in controls. Moreover, in control cells
caffeine shortened G(2) and increased chromosomal damage 7-fold, while in
ataxia telangiectasia cells
caffeine only trebled aberration yield without shortening G(2). As
caffeine is an inhibitor of ATM
kinase, these results suggest the existence of some redundant ATM-independent checkpoint in G(2) of
ataxia telangiectasia cells. The differential response to
caffeine of
ataxia telangiectasia and control lymphocytes 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 the other controlling G(2) timing. While in controls both subpathways may be mediated by ATM
kinase, in
ataxia telangiectasia cells
caffeine-sensitive ATR
kinase and the
caffeine-insensitive
DNA-PK
kinases might be responsible for DNA repair and the G(2) delay subpathways, respectively. Confirmation of this model in
ataxia telangiectasia cells with another cell type in which both subpathways are mediated by
DNA-PK should define whether a metylxanthine such as
caffeine may also have an additional direct inhibitory effect on DNA repair.