Molecular Mechanisms of DNA Damage and Repair

14 Jun 2023 Doctoral Thesis

Student: Mgr. Ivo Durník
Supervisor: RNDr. Petr Kulhánek, Ph.D.
Group: Laboratory of Computational Chemistry
Reader: doc. RNDr. Karel Berka, Ph.D., doc. RNDr. Michal Čajan, Ph.D.


Maintenance of genetic information stored in DNA is a perpetual battle between processes damaging DNA and processes repairing such damage. Any DNA damage escaping its repair can eventually result in cell death, aging, or cancer. The long-term evolution pressure caused the development of very efficient repair mechanisms. Thus, in this thesis, we aimed to decipher the molecular nature of the selected repair mechanism as a possible inspiration for advancing cancer therapies. Obtained results were published in five peer-reviewed articles. Three of them are computational studies focusing on mismatched DNA. Two additional studies combine experiments and theory to better describe supramolecular systems with potential therapeutic applications. In the first part, we show that mismatched base pairs can be discriminated from canonical base pairs by opening into the minor groove. We also showed that the dsDNA sequence modulates mismatch discrimination. In the second part, we focus on two supramolecular systems: a G-quadruplex stabilized by an aromatic probe and a host-guest complex based on beta-cyclodextrin. Here, we managed to provide structural and energetical details that were not accessible through experiments. The data obtained can assist in the future rational design of supramolecular systems, leading to the development of more effective anticancer drugs.


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