title: The topoisomerase IIbeta circular clamp arrests transcription and signals a 26S proteasome pathway.
abstract: It has been proposed that the topoisomerase II (TOP2)beta-DNA covalent complex arrests transcription and triggers 26S proteasome-mediated degradation of TOP2beta. It is unclear whether the initial trigger for proteasomal degradation is due to DNA damage or transcriptional arrest. 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. Arrest of transcription, which is TOP2beta-dependent, is accompanied by proteasomal degradation of TOP2beta. Different from TOP2 poisons and other DNA-damaging agents, ICRF-193 did not induce proteasomal degradation of the large subunit of RNA polymerase II. These results suggest that proteasomal degradation of TOP2beta induced by the TOP2-DNA covalent complex or the TOP2 circular clamp is due to transcriptional arrest but not DNA damage. By contrast, degradation of the large subunit of RNA polymerase II is due to a DNA-damage signal.
authors.affiliation: Department of Pharmacology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854-5635, USA.
authors.forename: Hai
authors.initials: H
authors.lastname: Xiao
authors.forename: Yong
authors.initials: Y
authors.lastname: Mao
authors.forename: Shyamal D
authors.initials: SD
authors.lastname: Desai
authors.forename: Nai
authors.initials: N
authors.lastname: Zhou
authors.forename: Chun-Yuan
authors.initials: CY
authors.lastname: Ting
authors.forename: Jaulang
authors.initials: J
authors.lastname: Hwang
authors.forename: Leroy F
authors.initials: LF
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins; D054659:Diketopiperazines; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D010447:Peptide Hydrolases / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D015398:Signal Transduction / Q000187:drug effects; D013713:Teniposide / Q000494:pharmacology; D059005:Topoisomerase II Inhibitors; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; D054659:Diketopiperazines; D004791:Enzyme Inhibitors; D010879:Piperazines; D059005:Topoisomerase II Inhibitors; D016159:Tumor Suppressor Protein p53; C070899:4,4'-(1,2-dimethyl-1,2-ethanediyl)bis-2,6-piperazinedione; D013713:Teniposide; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D004250:DNA Topoisomerases, Type II