Mechanisms by which GSK3β inhibition enhances nonhomologous end-joining repair of IR-induced double strand breaks
Neurocognitive deficits from cranial irradiation are serious side effects from treatment of leukemias, especially in children. We have previously found that lithium, an inhibitor of the enzyme glycogen synthase kinase-3_ (GSK3_), can protect neurons but not cancer cells from radiation induced cell death and prevent cognitive deficits in irradiated mice. This occurs through enhanced repair of DNA damage generated by radiation. In this proposed study, we will further investigate the mechanism by which inhibition of GSK3_ increases DNA repair and confirm that inhibition of GSK3_ does not protect leukemia cells. Importantly, we will validate our result in transgenic mice. We hypothesize that the effects of GSK3_ inhibition are through stabilizing important proteins involved in DNA repair following radiation. Understanding the pathways involved in neuroprotection will allow for the discovery of novel targets and generation of new compounds for use to prevent the cognitive side effects of cranial irradiation, especially in children.