Processing of Physiologically–Induced DNA DSB is Defective in Purkinje Cells in Amouse Model of the Human Genetic Disorder Ataxia-Telangiectasia

ATM, the protein defective in A-T plays a central role in responding to radiation-induced DNA double strand breaks (DSB) and failure to repair a subset of these breaks appears to be responsible for the radiosensitivity that characterizes this syndrome.Recent evidence suggests that the subset of breaks are those with topoisomerase II (TopoII) blocked ends in proliferating cells. Normal neuronal activity has also been shown to induce the formation of DNA DSB, mediated by TopoII, at the promoters of a subset of immediate early response genes (IEGs). These genes are crucial for experience-driven synaptic changes associated with learning and memory and interference with repairing these breaks causes memory deficits in mice. Since cerebellar atrophy involves primarily loss of Purkinje cells, we determined whether physical activity would also induce DNA DSB at the same promoters and abnormalities would be observed in a movement disorder such as A-T, reflecting a physiological role for ATM in the absence of radiation- induced DNA damage. We present evidence in an Atm-deficient mouse that both basal and physical activity-induced levels of DNA DSB are elevated in Purkinje cells compared to levels in Atm+/+ mice. We also demonstrate for the first time that increased numbers of DNA DSB are observed in Atm-/- Purkinje cell and that repair of these DNA DSBs is less efficient in Purkinje cells from Atm-deficient mice. The predominance of physiologically (non-DNA damage)-induced breaks in Purkinje cells is a novel observation since these breaks are found in a cell type that is most vulnerable in patients.We are in the process of investigating the mechanism involved.