TDP2/TTRAP Is the Major 5′-Tyrosyl DNA Phosphodiesterase Activity in Vertebrate Cells and Is Critical for Cellular Resistance to Topoisomerase II-induced DNA Damage

Topoisomerase II (Top2) activity involves an intermediate in which the topoisomerase is covalently bound to a DNA double-strand break via a 5′-phosphotyrosyl bond. Although these intermediates are normally transient, they can be stabilized by antitumor agents that act as Top2 “poisons,” resulting in...

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Autores: Zeng, Zhihong, Cortés Ledesma, Felipe, El Khamisy, Sherif F., Caldecott, Keith W.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2011
País:España
Institución:Universidad de Sevilla (US)
Repositorio:idUS. Depósito de Investigación de la Universidad de Sevilla
OAI Identifier:oai:idus.us.es:11441/64488
Acceso en línea:http://hdl.handle.net/11441/64488
https://doi.org/10.1074/jbc.M110.181016
Access Level:acceso abierto
Palabra clave:Cancer Therapy
DNA Damage
DNA Repair
DNA Topoisomerase
Phosphodiesterases
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spelling TDP2/TTRAP Is the Major 5′-Tyrosyl DNA Phosphodiesterase Activity in Vertebrate Cells and Is Critical for Cellular Resistance to Topoisomerase II-induced DNA DamageZeng, ZhihongCortés Ledesma, FelipeEl Khamisy, Sherif F.Caldecott, Keith W.Cancer TherapyDNA DamageDNA RepairDNA TopoisomerasePhosphodiesterasesTopoisomerase II (Top2) activity involves an intermediate in which the topoisomerase is covalently bound to a DNA double-strand break via a 5′-phosphotyrosyl bond. Although these intermediates are normally transient, they can be stabilized by antitumor agents that act as Top2 “poisons,” resulting in the induction of cytotoxic double-strand breaks, and they are implicated in the formation of site-specific translocations that are commonly associated with cancer. Recently, we revealed that TRAF and TNF receptor-associated protein (TTRAP) is a 5′-tyrosyl DNA phosphodiesterase (5′-TDP) that can cleave 5′-phosphotyrosyl bonds, and we denoted this protein tyrosyl DNA phosphodiesterase-2 (TDP2). Here, we have generated TDP2-deleted DT40 cells, and we show that TDP2 is the major if not the only 5′-TDP activity present in vertebrate cells. We also show that TDP2-deleted DT40 cells are highly sensitive to the anticancer Top2 poison, etoposide, but are not hypersensitive to the Top1 poison camptothecin or the DNA-alkyating agent methyl methanesulfonate. These data identify an important mechanism for resistance to Top2-induced chromosome breakage and raise the possibility that TDP2 is a significant factor in cancer development and treatment.American Society for Biochemistry and Molecular Biology2011info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/11441/64488https://doi.org/10.1074/jbc.M110.181016reponame:idUS. Depósito de Investigación de la Universidad de Sevillainstname:Universidad de Sevilla (US)InglésJournal of Biological Chemistry, 286 (1), 403-409.http://dx.doi.org/ 10.1074/jbc.M110.181016info:eu-repo/semantics/openAccessoai:idus.us.es:11441/644882026-06-17T12:51:07Z
dc.title.none.fl_str_mv TDP2/TTRAP Is the Major 5′-Tyrosyl DNA Phosphodiesterase Activity in Vertebrate Cells and Is Critical for Cellular Resistance to Topoisomerase II-induced DNA Damage
title TDP2/TTRAP Is the Major 5′-Tyrosyl DNA Phosphodiesterase Activity in Vertebrate Cells and Is Critical for Cellular Resistance to Topoisomerase II-induced DNA Damage
spellingShingle TDP2/TTRAP Is the Major 5′-Tyrosyl DNA Phosphodiesterase Activity in Vertebrate Cells and Is Critical for Cellular Resistance to Topoisomerase II-induced DNA Damage
Zeng, Zhihong
Cancer Therapy
DNA Damage
DNA Repair
DNA Topoisomerase
Phosphodiesterases
title_short TDP2/TTRAP Is the Major 5′-Tyrosyl DNA Phosphodiesterase Activity in Vertebrate Cells and Is Critical for Cellular Resistance to Topoisomerase II-induced DNA Damage
title_full TDP2/TTRAP Is the Major 5′-Tyrosyl DNA Phosphodiesterase Activity in Vertebrate Cells and Is Critical for Cellular Resistance to Topoisomerase II-induced DNA Damage
title_fullStr TDP2/TTRAP Is the Major 5′-Tyrosyl DNA Phosphodiesterase Activity in Vertebrate Cells and Is Critical for Cellular Resistance to Topoisomerase II-induced DNA Damage
title_full_unstemmed TDP2/TTRAP Is the Major 5′-Tyrosyl DNA Phosphodiesterase Activity in Vertebrate Cells and Is Critical for Cellular Resistance to Topoisomerase II-induced DNA Damage
title_sort TDP2/TTRAP Is the Major 5′-Tyrosyl DNA Phosphodiesterase Activity in Vertebrate Cells and Is Critical for Cellular Resistance to Topoisomerase II-induced DNA Damage
dc.creator.none.fl_str_mv Zeng, Zhihong
Cortés Ledesma, Felipe
El Khamisy, Sherif F.
Caldecott, Keith W.
author Zeng, Zhihong
author_facet Zeng, Zhihong
Cortés Ledesma, Felipe
El Khamisy, Sherif F.
Caldecott, Keith W.
author_role author
author2 Cortés Ledesma, Felipe
El Khamisy, Sherif F.
Caldecott, Keith W.
author2_role author
author
author
dc.subject.none.fl_str_mv Cancer Therapy
DNA Damage
DNA Repair
DNA Topoisomerase
Phosphodiesterases
topic Cancer Therapy
DNA Damage
DNA Repair
DNA Topoisomerase
Phosphodiesterases
description Topoisomerase II (Top2) activity involves an intermediate in which the topoisomerase is covalently bound to a DNA double-strand break via a 5′-phosphotyrosyl bond. Although these intermediates are normally transient, they can be stabilized by antitumor agents that act as Top2 “poisons,” resulting in the induction of cytotoxic double-strand breaks, and they are implicated in the formation of site-specific translocations that are commonly associated with cancer. Recently, we revealed that TRAF and TNF receptor-associated protein (TTRAP) is a 5′-tyrosyl DNA phosphodiesterase (5′-TDP) that can cleave 5′-phosphotyrosyl bonds, and we denoted this protein tyrosyl DNA phosphodiesterase-2 (TDP2). Here, we have generated TDP2-deleted DT40 cells, and we show that TDP2 is the major if not the only 5′-TDP activity present in vertebrate cells. We also show that TDP2-deleted DT40 cells are highly sensitive to the anticancer Top2 poison, etoposide, but are not hypersensitive to the Top1 poison camptothecin or the DNA-alkyating agent methyl methanesulfonate. These data identify an important mechanism for resistance to Top2-induced chromosome breakage and raise the possibility that TDP2 is a significant factor in cancer development and treatment.
publishDate 2011
dc.date.none.fl_str_mv 2011
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11441/64488
https://doi.org/10.1074/jbc.M110.181016
url http://hdl.handle.net/11441/64488
https://doi.org/10.1074/jbc.M110.181016
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Journal of Biological Chemistry, 286 (1), 403-409.
http://dx.doi.org/ 10.1074/jbc.M110.181016
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology
publisher.none.fl_str_mv American Society for Biochemistry and Molecular Biology
dc.source.none.fl_str_mv reponame:idUS. Depósito de Investigación de la Universidad de Sevilla
instname:Universidad de Sevilla (US)
instname_str Universidad de Sevilla (US)
reponame_str idUS. Depósito de Investigación de la Universidad de Sevilla
collection idUS. Depósito de Investigación de la Universidad de Sevilla
repository.name.fl_str_mv
repository.mail.fl_str_mv
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