Project 171666

Project summary: Reactive oxygen species are highly unstable molecules and are produced, e.g., by mitochondrial respiration and activated neutrophils. These reactive oxygen species can attack and destroy various cellular macromolecules such as proteins or enzymes to cause functional inactivation, thereby leading to several human disorders, such as amyotrophic lateral sclerosis, Down's syndrome, and Alzheimer's disease. Previous research: (What has been done already?) We discovered that the protein GAPDH can form an association with the DNA repair enzyme APE1, which functions to maintain the integrity of the genome. We show that GAPDH converts the inactive form of APE1, that is, the oxidized APE1 caused by reactive oxygen species, to the active form that is needed to repair damaged DNA. Reducing the level of GAPDH decreased the activity of APE1 and caused the DNA to accumulate lesions. Such lesions if not repaired can initiate the formation of cancer cells. Project description: (What is being studied and how the study will be conducted?) We believe that GAPDH has the ability to maintian the redox state of a key DNA repair enzyme APE1. We plan to show that inactivated APE1 is unable to process in vivo DNA lesions and therefore causes a range of biological consequences. Impact and relevance: (How will our studies help?) We predict that GAPDH may act to protect APE1 protein which is susceptible to reactive oxygen species-induced structural damage. We believe that this is required in neurodegenerative diseases such that it prevents accumulation of genotoxic lesions that could trigger cell death. Moreover, defects in GAPDH function might serve to predict individuals who are at risk of developing cancers

investigating the role of GAPDH in reactivating oxidized forms of the DNA repair enzyme APE1