ATM and Regulation of Protein Homeostasis in Human Cells

The Ataxia-Telangiectasia mutated (ATM) protein is a key regulator of checkpoint activation and homologous recombination in response to DNA double strand breaks (DSBs). In addition, ATM can be activated independently of MRN and DNA through direct oxidation, and ATM acts a redox sensor for oxidative stress in human cells. We have isolated and characterized separation-of-function mutants for each of the pathways and have investigated the effects of these changes on ATM phosphorylation events in response to a variety of stress conditions, in order to determine how these distinct pathways each contribute to the overall ATM response. One notable consequence of loss of the oxidative stress pathway is the appearance of widespread protein aggregation in human cells, which is interesting considering the common links between neurodegenerative disorders and defects in protein homeostasis. Our current studies investigate how each activation pathway affects protein stability and aggregation, and the mechanisms underlying these outcomes. These and other topics of ATM regulation will be discussed.