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M.S., Tongji Medical University - 2004
Thesis Advisor: Leroy Liu, Ph.D.
Graduate Program in Cellular & Molecular Pharmacology
Pharmacology Department Conference Room,
4th floor, RWJMS Research Tower
Wednesday, August 24, 2011
Topoisomerase cleavage complexes are central to the action of many potent therapeutics. Processing/repair of topoisomerase cleavage complexes (covalent topoisomerase-DNA adducts) has been proposed to involve proteasome-mediated degradation of covalently bound topoisomerases, resulting in exposure of otherwise topoisomerase-concealed DNA strand breaks. Processing/repair of topoisomerase I cleavage complexes has been reported to occur through an ubiquitin-dependent 26S proteasome pathway. In the current studies, we show that degradation of topoisomerase II‚ cleavage complexes occurs through a novel ubiquitin-independent mechanism that requires only the ATPases and the 20S core of the proteasome. We propose that upon arrest of the transcription elongation complex by the Top2‚ cleavage complex, the polymerase-associated 19S proteasome ATPases initiate the assembly of an ATPases-20S core complex for degradation of Top2‚. The differential employment of ubiquitin-dependent and ubiquitin-independent mechanisms for proteasome-dependent degradation of topoisomerase-DNA covalent complexes is discussed.