Endogenous topoisomerase II-mediated DNA breaks drive thymic cancer predisposition linked to ATM deficiency

Alejandro Álvarez-Quilón, José Terrón-Bautista, Irene Delgado-Sainz, Almudena Serrano-Benítez, Rocío Romero-Granados, Pedro Manuel Martínez-García, Silvia Jimeno-González, Cristina Bernal-Lozano, Cristina Quintero, Lourdes García-Quintanilla and Felipe Cortés-Ledesma ()
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Alejandro Álvarez-Quilón: CSIC-Universidad de Sevilla-Universidad Pablo de Olavide
José Terrón-Bautista: CSIC-Universidad de Sevilla-Universidad Pablo de Olavide
Irene Delgado-Sainz: CSIC-Universidad de Sevilla-Universidad Pablo de Olavide
Almudena Serrano-Benítez: CSIC-Universidad de Sevilla-Universidad Pablo de Olavide
Rocío Romero-Granados: CSIC-Universidad de Sevilla-Universidad Pablo de Olavide
Pedro Manuel Martínez-García: CSIC-Universidad de Sevilla-Universidad Pablo de Olavide
Silvia Jimeno-González: CSIC-Universidad de Sevilla-Universidad Pablo de Olavide
Cristina Bernal-Lozano: CSIC-Universidad de Sevilla-Universidad Pablo de Olavide
Cristina Quintero: CSIC-Universidad de Sevilla-Universidad Pablo de Olavide
Lourdes García-Quintanilla: CSIC-Universidad de Sevilla-Universidad Pablo de Olavide
Felipe Cortés-Ledesma: CSIC-Universidad de Sevilla-Universidad Pablo de Olavide

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-14638-w

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