Repair of covalent protein-DNA complexes

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I am studying the repair of covalent topoisomerase-DNA complexes. A number of anti-cancer drugs that are in clinical use today induce the formation of such complexes. The resulting DNA strand breaks are particularly difficult to repair since a large protein, which is chemically linked to the DNA, covers the DNA end at the break. Unrepaired DNA double-strand breaks lead to cell death, especially in cells that are dividing rapidly, such as cancer cells. The DNA repair activity Tdp1 removes covalently trapped topoisomerase I from the DNA. Thus, a tandem drug regimen with a Tdp1 inhibitor and a drug that creates a substrate for Tdp1, e.g. the topoisomerase IB-specific anti-cancer drug camptothecin could potentiate the cytotoxicity and efficacy of both drugs. Therefore, I propose to search for drugs that inhibit Tdp1. A mutation in Tdp1 causes the neurodegenerative disorder SCAN1. I propose to identify the molecular mechanism of this disease using a mouse model. These experiments will contribute to understanding the relationship between DNA repair and neurodegeneration.To apply my expertise with Tdp1 to another human health problem I propose to evaluate the suitability of Trypanosoma brucei Tdp1 as a drug target for anti-parasitic therapy to fight African sleeping sickness.