The DNA of the human genome is very long, about 2 meters, but it is confined in each of our cells to the volume of the nucleus, a tiny sphere only about 10 microns in diameter. Obviously, this is only possible because DNA is coiled and packed into highly complex structures. In fact, the very structure of DNA, a double helix, already confers an inherent degree of coiling. Accessing genetic information, either for continuous expression, or at specific moments for its duplication and distribution during cell division, is therefore a major challenge; aberrant coils, knots and other topological problems inevitably appear. Topoisomerases are highly specialized enzymes that solve these topological problems, but use a cut-and-reseal mechanism that, when uncontrolled, can lead to the generation of DNA breaks that can compromise cell survival and the stability of the genome. This aberrant action of topoisomerases, in addition to being a potential endogenous source of DNA damage, constitutes the therapeutic basis for a series of widely used antitumor compounds that target the particularly active genome of cancer cells by “poisoning” topoisomerase activity. Imbalances in DNA topoisomerase activity can therefore compromise cell survival and genome integrity, entailing serious consequences for human health, such as developmental and degenerative problems and, very importantly, neoplastic transformation processes and their subsequent response to treatment.
This project aimed at acquiring a comprehensive picture of the dynamics of topoisomerase activity, how it is regulated to integrate different aspects of genome dynamics, how an imbalance in these processes can lead to the appearance of pathological DNA breaks, and how cells specifically respond to these lesions to maintain genome stability.
