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VICERRECTORADO DE INVESTIGACIÓN | |||
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Proyecto de investigación
Topoisomerase-induced DNA breaks: link with cancer and neurodegeneration
Responsable: Felipe Cortés Ledesma
Tipo de Proyecto/Ayuda: 7º Programa Marco de la U.E.
Referencia: 268466
Web: http://cordis.europa.eu/projects/rcn/96160_en.html
Fecha de Inicio: 01-09-2010
Fecha de Finalización: 31-08-2013
Empresa/Organismo financiador/es:
- Comisión Europea
Resumen del proyecto:
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 tumorigenesis. 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 progressive neurodegenerative disease. Fully understanding the mechanisms and regulation governing the repair of topoisomerase-induced damage is therefore extremely important to gain new insights into two processes that are a main concern to human health: (a) cancer, both its onset and its therapy, and (b) neurodegenerative disease. We will combine the use of animal models with biochemistry and molecular and cellular biology techniques to explore different aspects of the repair of topoisomerase-induced breaks. We will mainly focus on our recently identified tyrosyl DNA phosphodiesterase 2 (TDP2), studying its mechanism of action and regulation with special attention to the possible implications in cancer and neurodegeneration.