Antonino Buccheri

Topoisomerase in Cancer Research

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Topoisomerase in Cancer Research

DNA topoisomerases are enzymes that control and modify the topological states of DNA in cells. Human topoisomerase I is composed of 765 aminoacids, and the crystal structure of the N-terminal truncated protein (topo70) together with proteolytic experiments show that the enzyme is composed of four different domains: N-terminal domain (amino acids 1-206), core domain (aminoacid 207-635), linker domain (636-712), and C-terminal domain (amino acids 713-765). The catalytic cycle is composed by five subsequent steps: binding of the enzyme to DNA; DNA cleavage; controlled rotation of the DNA scissile-strand; DNA religation; DNA release. Human topoisomerase I is of significant medical interest being the only target of the antitumor drug camptothecin (CPT). CPT reversibly binds to the covalent intermediate DNA-enzyme, stabilizing the cleavable complex and reducing the rate of religation. The stalled topoisomerase I collides with the progression of the replication fork producing lethal double-strand DNA breaks and cell death.

In our laboratory, we are interested in the characterization of the mechanism of action of this enzyme and in the elucidation of the principles governing the drug interaction in order to develop more efficient drug. In detail at the moment we are studying topoisomerase I mutants displaying drug-resistance correlating their structural dynamical properties with their varied function and their different answer to the drug. We are also involved in the understanding of the fine details of the protein drug interaction through coupled spectroscopic studies and ‘ab initio’ calculations of the drug in solution. Finally, we are working on the description of the structure of the enzyme in its open conformation.

Comment (5)

  • Anonymous| 28 November 2019


  • site club de loteria| 16 January 2020

    Você tem a imagem do seu sonho no seu consciente.

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  • Anonymous| 25 January 2021


  • web site| 10 February 2021

    Desembara├žado no: Acesso em: 21 a maio com 2011.

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