Repair of covalent protein-DNA complexes

我正在研究共价拓扑异构酶- dna复合物的修复。目前临床使用的许多抗癌药物都能诱导这种复合物的形成。DNA链断裂尤其难以修复，因为一种与DNA化学连接的大蛋白质覆盖在断裂的DNA末端。未修复的DNA双链断裂导致细胞死亡，特别是在快速分裂的细胞中，如癌细胞。DNA修复活性Tdp1从DNA中去除共价捕获的拓扑异构酶I。因此，一种Tdp1抑制剂和一种为Tdp1创造底物的药物（如ib特异性拓扑异构酶抗癌药物喜树碱）的串联用药方案可以增强两种药物的细胞毒性和疗效。因此，我建议寻找抑制Tdp1的药物。Tdp1的突变导致神经退行性疾病SCAN1。我建议用小鼠模型来确定这种疾病的分子机制。这些实验将有助于理解DNA修复和神经退行性变之间的关系。为了将我在Tdp1方面的专业知识应用于另一个人类健康问题，我建议评估布鲁氏锥虫Tdp1作为抗寄生虫治疗药物靶点的适用性，以对抗非洲昏睡病。

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.