期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 286, 期 1, 页码 403-409出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M110.181016
关键词
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资金
- Medical Research Council [G0600776, G0901606]
- Marie Curie IntraEuropean Fellowship [2007-2-1-IEF-221222]
- Wellcome Trust [085284]
- MRC [G0600776, G0901606] Funding Source: UKRI
- Cancer Research UK [13078] Funding Source: researchfish
- Medical Research Council [G0901606, G0600776, G0801130B] Funding Source: researchfish
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.
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