![]() This form of DNA lesion is due to accumulation of the covalent intermediate of the TOP reaction, often referred to as the TOP cleavable or cleavage complex ( 1, 2). By contrast, degradation of the large subunit of RNA polymerase II is due to a DNA-damage signal.ĭNA topoisomerase (TOP)-mediated DNA damage (i.e., TOP–DNA covalent complexes) is an important form of DNA lesion that can be induced by xenobiotics (e.g., antibiotics and anticancer drugs), DNA structural perturbations (e.g., UV and carcinogen–DNA adducts), and physiological stresses (e.g., thiol stress and acidic pH) ( 1, 2). These results suggest that proteasomal degradation of TOP2β induced by the TOP2–DNA covalent complex or the TOP2 circular clamp is due to transcriptional arrest but not DNA damage. ![]() Different from TOP2 poisons and other DNA-damaging agents, ICRF-193 did not induce proteasomal degradation of the large subunit of RNA polymerase II. Arrest of transcription, which is TOP2β-dependent, is accompanied by proteasomal degradation of TOP2β. In the current study we show that the TOP2 catalytic inhibitor 4,4-(2,3-butanediyl)-bis(2,6-piperazinedione) (ICRF-193), which traps TOP2 into a circular clamp rather than the TOP2–DNA covalent complex, can also arrest transcription. It is unclear whether the initial trigger for proteasomal degradation is due to DNA damage or transcriptional arrest. It has been proposed that the topoisomerase II (TOP2)β–DNA covalent complex arrests transcription and triggers 26S proteasome-mediated degradation of TOP2β.
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