Grant: Project Grant

The cells in our body are routinely exposed to different types of stress, such as agents that damage DNA, and 'environmental' stressors that affect the function of cells. Environmental stressors include agents that induce reactive oxygen species which can damage cells. Importantly, the presence of excessive reactive oxygen species in brain neurons has been associated with a number of neurodegenerative diseases. DEAD box proteins are RNA unwinding proteins whose main role is to alter the structure of RNA, thereby affecting the amount and types of proteins expressed in cells. We are working on a DEAD box gene called DEAD Box 1, or DDX1, originally identified in my lab. Over the last few years, we have shown that DDX1 helps to repair a type of DNA damage called 'double strand breaks'. We have also shown that DDX1 is important for the resolution of stress caused by agents that induce reactive oxygen species. Intriguingly, we have recently discovered that DDX1 interacts with DNA repair proteins (such as ATM) associated with neurodegeneration. Mutations in the ATM gene are the underlying cause of ataxia telangiectasia, an inherited neurodegenerative disease that affects children and adults. Our combined research findings have led us to hypothesize that DDX1 helps to resolve stress in neurons. Thus, we propose that inability of DDX1 to carry out its normal function keeps cells in a state of stress, a condition that leads to premature cell death in neurons. The goal of this proposal is to determine how DDX1 resolves stress with a focus on understanding DDX1's mechanism of action in cells that are defective in ATM, as well as in neuronal cells. Thus, we will use cells from patients with ataxia telangiectasia and neuronal cells to examine the molecules that DDX1 interacts with under normal versus stress conditions. Our long term goal is to determine whether DDX1 and its partners could be used to either prevent or slow down neuronal cell death in susceptible individuals.