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J Biol Chem, Vol. 275, Issue 17, 13109-13117, April 28, 2000

Degradation of DNA Topoisomerase I by a Novel Trypsin-like Serine Protease in Proliferating Human T Lymphocytes^*

Hui-Jye Chen^§, Ching-Long Hwong^§, Cheng-Hsu Wang^¶, and Jaulang Hwang^§

From the  Institute of Biochemistry, School of Life Science, National Yang-Ming University, Taipei 112, Taiwan, the ^§ Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan, and the ^¶ Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Taipei 105, Taiwan

DNA topoisomerase I (Topo I) contributes to various important biological functions, and its activity is therefore likely regulated in response to different physiological conditions. Increases in both the synthesis and degradation of Topo I were previously shown to accompany phytohemagglutinin stimulation of proliferation in human peripheral T lymphocytes. The mechanism of this degradation of Topo I has now been investigated with both in vivo and in vitro assays. The activity of a nuclear protease that specifically degrades Topo I was induced in proliferating T lymphocytes. The full-length Topo I protein (100 kDa) was sequentially degraded to 97- and 82-kDa fragments both in vivo and in vitro. The initial site of proteolytic cleavage was mapped to the NH₂-terminal region of the enzyme. The degradation of Topo I in vitro was inhibited by aprotinin or soybean trypsin inhibitor, suggesting that the enzyme responsible is a trypsin-like serine protease. Furthermore, Topo I degradation by this protease was Mg²⁺-dependent. The Topo I-specific protease activity induced during T lymphocytes proliferation was not detected in Jurkat (human T cell leukemia) cells and various other tested human cancer cell lines, possibly explaining why the abundance of Topo I is increased in tumor cells.

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