Endogenous topoisomerase II-mediated DNA breaks drive thymic cancer predisposition linked to ATM deficiency
| العنوان: | Endogenous topoisomerase II-mediated DNA breaks drive thymic cancer predisposition linked to ATM deficiency |
|---|---|
| المؤلفون: | Almudena Serrano-Benitez, Pedro Manuel Martínez-García, Alejandro Álvarez-Quilón, Lourdes García-Quintanilla, Felipe Cortés-Ledesma, José Terrón-Bautista, Irene Delgado-Sainz, Cristina Quintero, Rocío Romero-Granados, Silvia Jimeno-González, Cristina Bernal-Lozano |
| المساهمون: | European Research Council, Regional Government of Andalusia (España), Ministerio de Ciencia e Innovación (España), Asociación Española Familia Ataxia Telangiectasia, Junta de Andalucía, Agencia Estatal de Investigación (España), Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía y Competitividad (España), European Commission, Ministerio de Educación, Cultura y Deporte (España), Universidad de Sevilla. Departamento de Genética |
| المصدر: | Repisalud Instituto de Salud Carlos III (ISCIII) idUS. Depósito de Investigación de la Universidad de Sevilla instname Digital.CSIC. Repositorio Institucional del CSIC Nature Communications Nature Communications, Vol 11, Iss 1, Pp 1-14 (2020) |
| بيانات النشر: | Nature Publishing Group, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Genomic instability, 0301 basic medicine, Lymphoma, DNA Repair, DNA damage, DNA repair, Science, General Physics and Astronomy, Double-strand DNA breaks, Endogeny, Ataxia Telangiectasia Mutated Proteins, DNA damage response, Article, General Biochemistry, Genetics and Molecular Biology, law.invention, Mice, 03 medical and health sciences, 0302 clinical medicine, law, medicine, Animals, Humans, DNA Breaks, Double-Stranded, lcsh:Science, Cancer, Mice, Knockout, Multidisciplinary, biology, Phosphoric Diester Hydrolases, Topoisomerase, Thymus Neoplasms, General Chemistry, medicine.disease, 3. Good health, DNA-Binding Proteins, DNA Topoisomerases, Type II, 030104 developmental biology, 030220 oncology & carcinogenesis, Dna breaks, Cancer research, biology.protein, Suppressor, lcsh:Q, Recombination |
| الوصف: | 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. This work has been funded with grants from the Spanish and Andalusian Government (SAF2010-21017, SAF2013-47343-P, SAF2014-55532-R, SAF2017-89619-R, CVI-7948, European Regional Development Fund), and the European Research Council (ERC-CoG-2014-647359); and with individual fellowships for AAQ (Formación Personal Investigador, BES-2011-047351, Ministerio de Ciencia e Innovación), JTB (Formación Profesorado Universitario, FPU15/03656, Ministerio de Educación, Cultura y Deporte) and ASB (Beca Predoctoral AEFAT, Asociación Española Familia Ataxia Telangiectasia). CABIMER is supported by the Andalusian Government. |
| وصف الملف: | application/pdf |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::6ffebc15e5b3de553075e378307f9817 http://hdl.handle.net/20.500.12105/9295 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....6ffebc15e5b3de553075e378307f9817 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |