2026-07-21T14:41:55Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/92952024-11-29T22:03:23Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597
Repisalud
author
Álvarez-Quilón, Alejandro
author
Terrón-Bautista, José
author
Delgado-Sainz, Irene
author
Serrano-Benítez, Almudena
author
Romero-Granados, Rocío
author
Martínez-García, Pedro Manuel
author
Jimeno-González, Silvia
author
Bernal-Lozano, Cristina
author
Quintero, Cristina
author
García-Quintanilla, Lourdes
author
Cortes-Ledesma, Felipe
funder
Unión Europea. Comisión Europea. European Research Council (ERC)
funder
Regional Government of Andalusia (España)
funder
Ministerio de Ciencia e Innovación (España)
funder
Asociación Española Familia Ataxia Telangiectasia
2020-03-20T17:19:12Z
2020-03-20T17:19:12Z
2020-02-14
Nat Commun. 2020;14;11(1):910.
10.1038/s41467-020-14638-w
2041-1723
2041-1723
Nature communications
32060399
http://hdl.handle.net/20.500.12105/9295
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.
eng
Endogenous topoisomerase II-mediated DNA breaks drive thymic cancer predisposition linked to ATM deficiency
journal article
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