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TDP2-Dependent Non-Homologous End-Joining Protects against Topoisomerase II-Induced DNA Breaks and Genome Instability in Cells and In Vivo

Opened Access TDP2-Dependent Non-Homologous End-Joining Protects against Topoisomerase II-Induced DNA Breaks and Genome Instability in Cells and In Vivo

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Autor: Gómez Herreros, Fernando
Romero Granados, Rocío
Zeng, Zhihong
Álvarez Quilón, Alejandro
Quintero Ruiz, María Cristina
Ju, Limei
Umans, Lieve
Vemeire, Liesbeth
Huylebroeck, Danny
Caldecott, Keith W.
Cortés Ledesma, Felipe
Fecha: 2013
Publicado en: Plos Genetics, 9 (3), e1003226-.
Tipo de documento: Artículo
Resumen: Anticancer topoisomerase >poisons> exploit the break-and-rejoining mechanism of topoisomerase II (TOP2) to generate TOP2-linked DNA double-strand breaks (DSBs). This characteristic underlies the clinical efficacy of TOP2 poisons, but is also implicated in chromosomal translocations and genome instability associated with secondary, treatment-related, haematological malignancy. Despite this relevance for cancer therapy, the mechanistic aspects governing repair of TOP2-induced DSBs and the physiological consequences that absent or aberrant repair can have are still poorly understood. To address these deficits, we employed cells and mice lacking tyrosyl DNA phosphodiesterase 2 (TDP2), an enzyme that hydrolyses 5′-phosphotyrosyl bonds at TOP2-associated DSBs, and studied their response to TOP2 poisons. Our results demonstrate that TDP2 functions in non-homologous end-joining (NHEJ) and liberates DSB termini that are competent for ligation. Moreover, we show that the absence of TDP2 in cell...
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Cita: Gómez Herreros, F., Romero Granados, R., Zeng, Z., Álvarez Quilón, A., Quintero Ruiz, M.C., Ju, L.,...,Cortés Ledesma, F. (2013). TDP2-Dependent Non-Homologous End-Joining Protects against Topoisomerase II-Induced DNA Breaks and Genome Instability in Cells and In Vivo. Plos Genetics, 9 (3), e1003226-.
Tamaño: 2.876Mb
Formato: PDF

URI: https://hdl.handle.net/11441/70142

DOI: 10.1371/journal.pgen.1003226

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