title: Transcription-dependent degradation of topoisomerase I-DNA covalent complexes.
abstract: Topoisomerase I (Top I)-DNA covalent complexes represent a unique type of DNA lesion whose repair and processing remain unclear. In this study, we show that Top I-DNA covalent complexes transiently arrest RNA transcription in normal nontransformed cells. Arrest of RNA transcription is coupled to activation of proteasomal degradation of Top I and the large subunit of RNA polymerase II. Recovery of transcription occurs gradually and depends on both proteasomal degradation of Top I and functional transcription-coupled repair (TCR). These results suggest that arrest of the RNA polymerase elongation complex by the Top I-DNA covalent complex triggers a 26S proteasome-mediated signaling pathway(s) leading to degradation of both Top I and the large subunit of RNA polymerase II. We propose that proteasomal degradation of Top I and RNA polymerase II precedes repair of the exposed single-strand breaks by TCR.
authors.affiliation: Department of Pharmacology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
authors.forename: Shyamal D
authors.initials: SD
authors.lastname: Desai
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Alexandra
authors.initials: A
authors.lastname: Rodriguez-Bauman
authors.forename: Jin-Ming
authors.initials: JM
authors.lastname: Yang
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Wu
authors.forename: Murugesan K
authors.initials: MK
authors.lastname: Gounder
authors.forename: Eric H
authors.initials: EH
authors.lastname: Rubin
authors.forename: Leroy F
authors.initials: LF
authors.lastname: Liu
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002166:Camptothecin / Q000494:pharmacology*; D002460:Cell Line; D006224:Cricetinae; D004247:DNA / Q000378:metabolism*; D004260:DNA Repair / Q000187:drug effects / Q000502:physiology; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000882:Haplorhini; D006801:Humans; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D046911:Macromolecular Substances; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex; D021122:Protein Subunits / Q000378:metabolism; D012319:RNA Polymerase II / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D059004:Topoisomerase I Inhibitors; D019772:Topotecan / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D046911:Macromolecular Substances; D019384:Nucleic Acid Synthesis Inhibitors; D021122:Protein Subunits; D025841:Small Ubiquitin-Related Modifier Proteins; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; D004247:DNA; D012319:RNA Polymerase II; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin