Cargando…

TDP2–Dependent Non-Homologous End-Joining Protects against Topoisomerase II–Induced DNA Breaks and Genome Instability in Cells and In Vivo

Anticancer topoisomerase “poisons” exploit the break-and-rejoining mechanism of topoisomerase II (TOP2) to generate TOP2-linked DNA double-strand breaks (DSBs). This characteristic underlies the clinical efficacy of TOP2 poisons, but is also implicated in chromosomal translocations and genome instab...

Descripción completa

Detalles Bibliográficos
Autores principales: Gómez-Herreros, Fernando, Romero-Granados, Rocío, Zeng, Zhihong, Álvarez-Quilón, Alejandro, Quintero, Cristina, Ju, Limei, Umans, Lieve, Vermeire, Liesbeth, Huylebroeck, Danny, Caldecott, Keith W., Cortés-Ledesma, Felipe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3592926/
https://www.ncbi.nlm.nih.gov/pubmed/23505375
http://dx.doi.org/10.1371/journal.pgen.1003226
_version_ 1782262210291040256
author Gómez-Herreros, Fernando
Romero-Granados, Rocío
Zeng, Zhihong
Álvarez-Quilón, Alejandro
Quintero, Cristina
Ju, Limei
Umans, Lieve
Vermeire, Liesbeth
Huylebroeck, Danny
Caldecott, Keith W.
Cortés-Ledesma, Felipe
author_facet Gómez-Herreros, Fernando
Romero-Granados, Rocío
Zeng, Zhihong
Álvarez-Quilón, Alejandro
Quintero, Cristina
Ju, Limei
Umans, Lieve
Vermeire, Liesbeth
Huylebroeck, Danny
Caldecott, Keith W.
Cortés-Ledesma, Felipe
author_sort Gómez-Herreros, Fernando
collection PubMed
description Anticancer topoisomerase “poisons” exploit the break-and-rejoining mechanism of topoisomerase II (TOP2) to generate TOP2-linked DNA double-strand breaks (DSBs). This characteristic underlies the clinical efficacy of TOP2 poisons, but is also implicated in chromosomal translocations and genome instability associated with secondary, treatment-related, haematological malignancy. Despite this relevance for cancer therapy, the mechanistic aspects governing repair of TOP2-induced DSBs and the physiological consequences that absent or aberrant repair can have are still poorly understood. To address these deficits, we employed cells and mice lacking tyrosyl DNA phosphodiesterase 2 (TDP2), an enzyme that hydrolyses 5′-phosphotyrosyl bonds at TOP2-associated DSBs, and studied their response to TOP2 poisons. Our results demonstrate that TDP2 functions in non-homologous end-joining (NHEJ) and liberates DSB termini that are competent for ligation. Moreover, we show that the absence of TDP2 in cells impairs not only the capacity to repair TOP2-induced DSBs but also the accuracy of the process, thus compromising genome integrity. Most importantly, we find this TDP2-dependent NHEJ mechanism to be physiologically relevant, as Tdp2-deleted mice are sensitive to TOP2-induced damage, displaying marked lymphoid toxicity, severe intestinal damage, and increased genome instability in the bone marrow. Collectively, our data reveal TDP2-mediated error-free NHEJ as an efficient and accurate mechanism to repair TOP2-induced DSBs. Given the widespread use of TOP2 poisons in cancer chemotherapy, this raises the possibility of TDP2 being an important etiological factor in the response of tumours to this type of agent and in the development of treatment-related malignancy.
format Online
Article
Text
id pubmed-3592926
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-35929262013-03-15 TDP2–Dependent Non-Homologous End-Joining Protects against Topoisomerase II–Induced DNA Breaks and Genome Instability in Cells and In Vivo Gómez-Herreros, Fernando Romero-Granados, Rocío Zeng, Zhihong Álvarez-Quilón, Alejandro Quintero, Cristina Ju, Limei Umans, Lieve Vermeire, Liesbeth Huylebroeck, Danny Caldecott, Keith W. Cortés-Ledesma, Felipe PLoS Genet Research Article Anticancer topoisomerase “poisons” exploit the break-and-rejoining mechanism of topoisomerase II (TOP2) to generate TOP2-linked DNA double-strand breaks (DSBs). This characteristic underlies the clinical efficacy of TOP2 poisons, but is also implicated in chromosomal translocations and genome instability associated with secondary, treatment-related, haematological malignancy. Despite this relevance for cancer therapy, the mechanistic aspects governing repair of TOP2-induced DSBs and the physiological consequences that absent or aberrant repair can have are still poorly understood. To address these deficits, we employed cells and mice lacking tyrosyl DNA phosphodiesterase 2 (TDP2), an enzyme that hydrolyses 5′-phosphotyrosyl bonds at TOP2-associated DSBs, and studied their response to TOP2 poisons. Our results demonstrate that TDP2 functions in non-homologous end-joining (NHEJ) and liberates DSB termini that are competent for ligation. Moreover, we show that the absence of TDP2 in cells impairs not only the capacity to repair TOP2-induced DSBs but also the accuracy of the process, thus compromising genome integrity. Most importantly, we find this TDP2-dependent NHEJ mechanism to be physiologically relevant, as Tdp2-deleted mice are sensitive to TOP2-induced damage, displaying marked lymphoid toxicity, severe intestinal damage, and increased genome instability in the bone marrow. Collectively, our data reveal TDP2-mediated error-free NHEJ as an efficient and accurate mechanism to repair TOP2-induced DSBs. Given the widespread use of TOP2 poisons in cancer chemotherapy, this raises the possibility of TDP2 being an important etiological factor in the response of tumours to this type of agent and in the development of treatment-related malignancy. Public Library of Science 2013-03-07 /pmc/articles/PMC3592926/ /pubmed/23505375 http://dx.doi.org/10.1371/journal.pgen.1003226 Text en © 2013 Gómez-Herreros et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Gómez-Herreros, Fernando
Romero-Granados, Rocío
Zeng, Zhihong
Álvarez-Quilón, Alejandro
Quintero, Cristina
Ju, Limei
Umans, Lieve
Vermeire, Liesbeth
Huylebroeck, Danny
Caldecott, Keith W.
Cortés-Ledesma, Felipe
TDP2–Dependent Non-Homologous End-Joining Protects against Topoisomerase II–Induced DNA Breaks and Genome Instability in Cells and In Vivo
title TDP2–Dependent Non-Homologous End-Joining Protects against Topoisomerase II–Induced DNA Breaks and Genome Instability in Cells and In Vivo
title_full TDP2–Dependent Non-Homologous End-Joining Protects against Topoisomerase II–Induced DNA Breaks and Genome Instability in Cells and In Vivo
title_fullStr TDP2–Dependent Non-Homologous End-Joining Protects against Topoisomerase II–Induced DNA Breaks and Genome Instability in Cells and In Vivo
title_full_unstemmed TDP2–Dependent Non-Homologous End-Joining Protects against Topoisomerase II–Induced DNA Breaks and Genome Instability in Cells and In Vivo
title_short TDP2–Dependent Non-Homologous End-Joining Protects against Topoisomerase II–Induced DNA Breaks and Genome Instability in Cells and In Vivo
title_sort tdp2–dependent non-homologous end-joining protects against topoisomerase ii–induced dna breaks and genome instability in cells and in vivo
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3592926/
https://www.ncbi.nlm.nih.gov/pubmed/23505375
http://dx.doi.org/10.1371/journal.pgen.1003226
work_keys_str_mv AT gomezherrerosfernando tdp2dependentnonhomologousendjoiningprotectsagainsttopoisomeraseiiinduceddnabreaksandgenomeinstabilityincellsandinvivo
AT romerogranadosrocio tdp2dependentnonhomologousendjoiningprotectsagainsttopoisomeraseiiinduceddnabreaksandgenomeinstabilityincellsandinvivo
AT zengzhihong tdp2dependentnonhomologousendjoiningprotectsagainsttopoisomeraseiiinduceddnabreaksandgenomeinstabilityincellsandinvivo
AT alvarezquilonalejandro tdp2dependentnonhomologousendjoiningprotectsagainsttopoisomeraseiiinduceddnabreaksandgenomeinstabilityincellsandinvivo
AT quinterocristina tdp2dependentnonhomologousendjoiningprotectsagainsttopoisomeraseiiinduceddnabreaksandgenomeinstabilityincellsandinvivo
AT julimei tdp2dependentnonhomologousendjoiningprotectsagainsttopoisomeraseiiinduceddnabreaksandgenomeinstabilityincellsandinvivo
AT umanslieve tdp2dependentnonhomologousendjoiningprotectsagainsttopoisomeraseiiinduceddnabreaksandgenomeinstabilityincellsandinvivo
AT vermeireliesbeth tdp2dependentnonhomologousendjoiningprotectsagainsttopoisomeraseiiinduceddnabreaksandgenomeinstabilityincellsandinvivo
AT huylebroeckdanny tdp2dependentnonhomologousendjoiningprotectsagainsttopoisomeraseiiinduceddnabreaksandgenomeinstabilityincellsandinvivo
AT caldecottkeithw tdp2dependentnonhomologousendjoiningprotectsagainsttopoisomeraseiiinduceddnabreaksandgenomeinstabilityincellsandinvivo
AT cortesledesmafelipe tdp2dependentnonhomologousendjoiningprotectsagainsttopoisomeraseiiinduceddnabreaksandgenomeinstabilityincellsandinvivo