Artículo
Endogenous topoisomerase II-mediated DNA breaks drive thymic cancer predisposition linked to ATM deficiency
Autor/es | Álvarez Quilón, Alejandro
Terrón Bautista, José Delgado Sainz, Irene Serrano Benítez, Almudena Romero Granados, Rocío Martínez García, Pedro Manuel Jimeno González, Silvia Bernal Lozano, Cristina Quintero, Cristina García Quintanilla, Lourdes Cortés Ledesma, Felipe |
Departamento | Universidad de Sevilla. Departamento de Genética |
Fecha de publicación | 2020 |
Fecha de depósito | 2020-04-22 |
Publicado en |
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Resumen | The ATM kinase is a master regulator of the DNA damage response to double-strand breaks (DSBs) and a well-established tumour suppressor whose loss is the cause of the neurodegenerative and cancer-prone syndrome ... The ATM kinase is a master regulator of the DNA damage response to double-strand breaks (DSBs) and a well-established tumour suppressor whose loss is the cause of the neurodegenerative and cancer-prone syndrome Ataxia-Telangiectasia (A-T). A-T patients and Atm−/− mouse models are particularly predisposed to develop lymphoid cancers derived from deficient repair of RAG-induced DSBs during V(D)J recombination. Here, we unexpectedly find that specifically disturbing the repair of DSBs produced by DNA topoisomerase II (TOP2) by genetically removing the highly specialised repair enzyme TDP2 increases the incidence of thymic tumours in Atm−/− mice. Furthermore, we find that TOP2 strongly colocalizes with RAG, both genome-wide and at V(D)J recombination sites, resulting in an increased endogenous chromosomal fragility of these regions. Thus, our findings demonstrate a strong causal relationship between endogenous TOP2-induced DSBs and cancer development, confirming these lesions as major drivers of ATM-deficient lymphoid malignancies, and potentially other conditions and cancer types. |
Identificador del proyecto | SAF2010-21017
SAF2013-47343-P SAF2014-55532-R SAF2017-89619-R CVI-7948 ERC-CoG-2014-647359 |
Cita | Álvarez Quilón, A., Terrón Bautista, J., Delgado Sainz, I., Serrano Benítez, A., Romero Granados, R., Martínez García, P.M.,...,Cortés Ledesma, F. (2020). Endogenous topoisomerase II-mediated DNA breaks drive thymic cancer predisposition linked to ATM deficiency. Nature Communications, 11 (1), 910-. |
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