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CBC/RBC Seminar with Bret Freudenthal

Visualizing Base Excision Repair in Chromatin

4:00 pm–5:00 pm
Beadle Center Room: E103
Additional Info: BEAD
Diana Bonham, (402) 472-2932,
One of the cells primary defenses against oxidative DNA damage is the base excision repair (BER) pathway. BER involves multiple factors that recognize and remove the damaged DNA base, prior to restoring the coding potential of the DNA with a new undamaged base. One of these BER factors is AP-endonuclease 1 (APE1), which processes AP-sites utilizing an AP-endonuclease activity. To date, our understanding of APE1 endonuclease activity has been driven by extensive studies on linear duplex DNA substrates. However, APE1 must find, access and repair DNA damage in the cell, where genomic DNA is packaged into nucleosomes and higher order chromatin structures. To understand how APE1 recognizes and processes AP-sites in the nucleosome, we utilized biochemical approaches and cryo-electron microscopy (cryo-EM). Pre-steady state kinetics determined that APE1 more readily processes AP-sites near the entry/exit site of the nucleosome compared to the nucleosome dyad. A Cryo-EM structure of APE1 bound to a nucleosome containing AP-site provided structural insight into how APE1 manipulates the nucleosomal DNA to perform catalysis. A single-molecule fluorescence approach determined that APE1 dynamically recognizes AP-sites at different translational and rotational position in the nucleosome. Together, our work provides unprecedented insight into the recognition and processing of DNA damage in the nucleosome by a base excision repair protein.

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This event originated in Biochemistry.