Interplay between DNA base excision repair and transcriptional regulation

PROJECT SUMMARY Guanine-rich G-quadruplex (G4) forming sequences are enriched at promoter proximal regions of the genome, in particular those of cancer and DNA repair-related genes. These regions are hot spots for oxidative lesions such as 8oxoG, coupling their repair via the base excision repair (BER) pathway to transcriptional regulation. Unfortunately, the molecular level interactions and mechanistic details of the coupled repair and gene regulation are not well understood, including the role of DNA structural dynamics, the precise mechanisms of repair and gene activation, the role of the N-terminal intrinsically disordered region and redox mechanism of BER protein apurinic/apyrimidinic endonuclease 1 (APE1). My goal as the leader of my independent research program at Fox Chase over the next five years is to empower and support a diverse team of young scientists to characterize the molecular-level interactions and coordination events coupling the repair of oxidative DNA damage and gene enhancement at G4 promoters in response to oxidative DNA damage. This will involve implementing a multi-disciplinary approach of techniques ranging from structural biology and single-molecule fluorescence to cell-based assays. By filling the current gaps in knowledge I will position my research program toward our long-term vision of developing novel therapeutics that can modulate transcription of key disease-associated genes through interfering with the key regulatory protein:protein and/or protein:DNA interactions.