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J. Biol. Chem.-2011-Zeng-403-9.pdf (2.33 MB)

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

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Version 2 2023-06-12, 06:35
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journal contribution
posted on 2023-06-12, 06:35 authored by Zhihong Zeng, Felipe Cortés-Ledesma, Sherif F El-Khamisy, Keith CaldecottKeith Caldecott
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.

History

Publication status

  • Published

File Version

  • Published version

Journal

Journal of Biological Chemistry

ISSN

0021-9258

Publisher

American Society for Biochemistry and Molecular Biology

Issue

1

Volume

286

Page range

403-409

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Notes

GDSC338

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2010-11-26

First Open Access (FOA) Date

2017-11-29

First Compliant Deposit (FCD) Date

2017-11-29

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