2026-05-21T23:03:33Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/92952024-11-29T22:03:23Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc 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 author 2020-02-14 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. 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 Endogenous topoisomerase II-mediated DNA breaks drive thymic cancer predisposition linked to ATM deficiency