SPLITTING THE ATM - DISTINCT REPAIR AND CHECKPOINT DEFECTS IN ATAXIA-TELANGIECTASIA

Ataxia-telangiectasia (A-T) is an autosomal recessive human disorder t hat because of its multisystem nature, is of interest to scientists an d clinicians from many disciplines. A-T patients have defects in the n eurological and immune systems, telangiectasia in the eyes and face, a nd are, in addition, cancer-prone and radiation-sensitive. A-T cell li nes have a range of diverse phenotypes including sensitivity to ionizi ng radiation and defects in cell-cycle checkpoint control. The ATM pro tein is a member of the PI 3-kinase-like superfamily, and it has been widely accepted that A-T cells represent mammalian cell-cycle checkpoi nt mutants and that the radiation sensitivity is a consequence of this defect However, several lines of evidence suggest that A-T cells have distinct repair and checkpoint defects. A-T cells therefore appear to barbour dual checkpoint/repair defects. Here, we review the evidence supporting this contention and consider its implications for an analys is of the A-T phenotype.