Project description
Genome topology and integrity: the role of enzyme-mediated DNA breaks
The human genome undergoes complex coiling and packing to fit into the tiny nucleus of each cell. Topoisomerase enzymes are central in genome topology and access by cutting and resealing DNA accordingly. However, errors in topoisomerase function can lead to persistent DNA strand breaks, compromise genome integrity and contribute to cancer development. Funded by the European Research Council, the TOPOmics project aims to comprehensively examine the dynamics of topoisomerase-induced DNA breaks, their repair, and the resulting impact on genome expression and integrity. Researchers will also look for new factors and pathways involved in the cellular response to these DNA lesions with potential diagnostic and therapeutic value.
Objective
DNA topoisomerases are conserved nuclear enzymes that regulate DNA topology by transiently cleaving and resealing the DNA molecule, fulfilling a fundamental role in virtually every aspect of chromosome metabolism. Nevertheless, erroneous or abortive topoisomerase activity can result in persistent DNA strand breaks with the enzyme covalently attached to 3’ or 5’ DNA ends by a phosphotyrosyl bond, an anomalous structure that can compromise cell survival and/or genome integrity with the consequent implications in tumourigenesis. This peculiarity of topoisomerase catalysis also underlies the anticancer efficacy of topoisomerase poisons, which inhibit the re-ligation step of the reaction inducing the formation of DNA breaks that preferentially target highly proliferating and/or repair defective tumour cells. In addition to this link with cancer therapy, defects in the repair of topoisomerase-induced DNA damage have been linked to neurological disease. Understanding the cellular response to topoisomerase-induced breaks is therefore key for important aspects of human health, with possible implications in the development of novel diagnostic, prognostic and therapeutic tools.
This project aims at acquiring a comprehensive picture of the dynamics of topoisomerase-induced DNA breaks: from their occurrence and repair to the consequences for genome expression and integrity. We rely on the development of completely novel assays to detect and isolate the different intermediates of topoisomerase-induced break repair, and which overcome major traditional limitations in the field. These tools are subsequently used to integrate the time-dependent and genome-wide distribution of the different steps and final outcomes of the process of topoisomerase-induced DNA break repair. Furthermore, we outline original proteomic and genetic screenings to identify novel factors and pathways specifically involved the cellular response to this important type of DNA lesion.
Fields of science
Programme(s)
Funding Scheme
ERC-COG - Consolidator GrantHost institution
28029 Madrid
Spain