DNA topoisomerases have a dual relationship with the genome. On the one hand, they are essential to solve the topological problems in the form of supercoiling, knots and tangles that are inherent to all DNA transactions. On the other hand, their intrinsic mechanism of action involves transient DNA cleavage, and can therefore result in the formation of highly cytotoxic and clastogenic DNA breaks, which not only occur accidentally during normal cellular metabolism, but also underlie the clinical efficacy of an important group of antitumour agents known as topoisomerase poisons. Imbalances in DNA topoisomerase activity can therefore compromise cell survival and genome integrity, entailing serious consequences and implications for human health, such as developmental and degenerative problems, and very importantly, neoplastic transformation processes and their subsequent response to treatment.
Our laboratory is interested in understanding how DNA topoisomerase activity is regulated to integrate different aspects of genome dynamics, from its 3D organisation and expression, to its duplication, condensation and segregation, 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. In order to do so, we undertake a comprehensive approach, combining detailed molecular, cellular and genome wide analyses with more physiological studies in mouse models, with a final aim at exploiting our discoveries in cancer prevention and treatment.
Publications
- (2017). ZATT (ZNF451)-mediated resolution of topoisomerase 2 DNA-protein cross-links.. Science 357, 1412-1416.
- (2017). Chd7 is indispensable for mammalian brain development through activation of a neuronal differentiation programme. Nat Commun 8, 14758.
- (2017). Regulation of human pol? by ATM-mediated phosphorylation during non-homologous end joining.. Dna Repair 51, 31-45.
- (2015). Non-redundant Functions of ATM and DNA-PKcs in Response to DNA Double-Strand Breaks.. Cell Reports 13, 1598-1609.
- (2014). TDP2 protects transcription from abortive Topoisomerase 2 activity and maintains normal neural function. Nat Genet 46, 516-521.
- (2014). ATM specifically mediates repair of double-strand breaks with blocked DNA ends. Nat Commun 5, 3347.
- (2013). TDP2-dependent non-homologous end-joining protects against topoisomerase II-induced DNA breaks and genome instability in cells and in vivo. PLoS Genet 9, e1003370.