RT Journal Article
T1 Endogenous topoisomerase II-mediated DNA breaks drive thymic cancer predisposition linked to ATM deficiency.
A1 Álvarez-Quilón, Alejandro
A1 Terrón-Bautista, José
A1 Delgado-Sainz, Irene
A1 Serrano-Benítez, Almudena
A1 Romero-Granados, Rocío
A1 Martínez-García, Pedro Manuel
A1 Jimeno-González, Silvia
A1 Bernal-Lozano, Cristina
A1 Quintero, Cristina
A1 García-Quintanilla, Lourdes
A1 Cortés-Ledesma, Felipe
AB 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.
YR 2020
FD 2020-02-14
LK http://hdl.handle.net/10668/15110
UL http://hdl.handle.net/10668/15110
LA en
DS RISalud
RD Apr 11, 2025