Environmental Molecular Sciences Laboratory

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Mechanisms of DNA damage access within the nucleosome during Base Excision Repair

Sunday, November 15, 2020
Principal Investigator: 
Bret Freudenthal
Lead Institution: 
University of Kansas Medical Center
Project ID: 

Despite the packaging of eukaryotic DNA into chromatin through repeating units known as the nucleosomes, it is constantly damaged via reactive oxygen species (ROS). 8oxo-guanine (8oxoG) is a common form of DNA damage resulting from the oxidation of guanine. If not repaired, 8oxoG is mutagenic, causing G to T transversion mutations that can initiate and promote genomic instability and ultimately human disease, such as cancer. The cells primary defense against 8oxoG is the base excision repair (BER) pathway. Two BER proteins involved in the initial recognition and removal of 8oxoG are 8oxoG DNA glycosylase 1 (OGG1) and apurinic/apyrimidinic endonuclease 1 (APE1). OGG1 and APE1 must find, access, and repair genomic DNA damage in complex chromatin structures, where the DNA is packaged into nucleosomes. To this end, the overarching goal of this proposal is to determine the structural basis for DNA damage recognition within the nucleosome by the base excision repair proteins OGG1 and APE1.