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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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Formato: | Texto |
Lenguaje: | English |
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American Society for Biochemistry and Molecular Biology
2011
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3012998/ https://www.ncbi.nlm.nih.gov/pubmed/21030584 http://dx.doi.org/10.1074/jbc.M110.181016 |
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author | Zeng, Zhihong Cortés-Ledesma, Felipe El Khamisy, Sherif F. Caldecott, Keith W. |
author_facet | Zeng, Zhihong Cortés-Ledesma, Felipe El Khamisy, Sherif F. Caldecott, Keith W. |
author_sort | Zeng, Zhihong |
collection | PubMed |
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. |
format | Text |
id | pubmed-3012998 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-30129982011-01-11 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 Cortés-Ledesma, Felipe El Khamisy, Sherif F. Caldecott, Keith W. J Biol Chem Cell Biology 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. American Society for Biochemistry and Molecular Biology 2011-01-07 2010-10-28 /pmc/articles/PMC3012998/ /pubmed/21030584 http://dx.doi.org/10.1074/jbc.M110.181016 Text en © 2011 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version full access. Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) applies to Author Choice Articles |
spellingShingle | Cell Biology Zeng, Zhihong Cortés-Ledesma, Felipe El Khamisy, Sherif F. Caldecott, Keith W. 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 |
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_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_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 |
topic | Cell Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3012998/ https://www.ncbi.nlm.nih.gov/pubmed/21030584 http://dx.doi.org/10.1074/jbc.M110.181016 |
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