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Prof. Dennis Gillingham “Chemical modifications of DNA and how they inspired a new method for target protein degradation”
October 17, 2022 @ 4:30 pm
Prof. Dennis Gillingham
University of Basel
“Chemical modifications of DNA and how they inspired a new method for target protein degradation”
Guanine is one of the most reactive bases in DNA and is often the site of action of DNA-modifying drugs. Alkylation damage at oxygen in position six of guanine is directly repaired by an unusual suicide protein known as methylguanine methyltransferase (MGMT). The protein performs an SN2 reaction at the alkylation damage, thus directly accepting the alkyl group. Once modified, the MGMT is then quickly degraded by the ubiquitin proteasome pathway. I will outline our discovery that copper catalysts selectively modify the O6 position of guanines in simple molecules and in DNA polymers. With simple access to these molecules in hand, we have recently invented new ways to use MGMT and MGMT-targeting molecules to control the degradation of proteins.