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PMID: 12640119 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Transcription-dependent degradation of topoisomerase I-DNA covalent complexes.

Molecular and cellular biology ·Vol. 23 ·No. 7 ·2003-04-00 ·Pages 2341-50

Desai SD, Zhang H, Rodriguez-Bauman A, Yang JM, Wu X, Gounder MK, Rubin EH, Liu LF

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.

MeSH Terms
Animals Antineoplastic Agents, Phytogenic/pharmacology Camptothecin/pharmacology Cell Line Cricetinae DNA/metabolism DNA Repair/drug effects,physiology DNA Topoisomerases, Type I/metabolism Drug Resistance, Neoplasm/physiology Enzyme Inhibitors/pharmacology Haplorhini Humans Lung/cytology,drug effects,metabolism Lymphocytes/cytology,drug effects,metabolism Macromolecular Substances Mice Mice, Nude Neoplasms/drug therapy,metabolism,pathology Nucleic Acid Synthesis Inhibitors/pharmacology Peptide Hydrolases/metabolism Proteasome Endopeptidase Complex Protein Subunits/metabolism RNA Polymerase II/antagonists & inhibitors,metabolism Signal Transduction/physiology Small Ubiquitin-Related Modifier Proteins/metabolism Topoisomerase I Inhibitors Topotecan/pharmacology Transcription, Genetic/drug effects,physiology Xenograft Model Antitumor Assays
Chemicals
Antineoplastic Agents, Phytogenic Enzyme Inhibitors Macromolecular Substances Nucleic Acid Synthesis Inhibitors Protein Subunits Small Ubiquitin-Related Modifier Proteins Topoisomerase I Inhibitors Topotecan DNA RNA Polymerase II Peptide Hydrolases Proteasome Endopeptidase Complex ATP dependent 26S protease DNA Topoisomerases, Type I Camptothecin
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Desai Shyamal D
Department of Pharmacology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
Zhang Hui
Rodriguez-Bauman Alexandra
Yang Jin-Ming
Wu Xiaohua
Gounder Murugesan K
Rubin Eric H
Liu Leroy F
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.23.7.2341-2350.2003
Published
2003-04-00
Pages
2341-50
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC150741
Subset
IM
Grants
NCI NIH HHS · R01 CA039662 · United States
NCI NIH HHS · CA 39662 · United States
NCI NIH HHS · CA 77433 · United States
NIGMS NIH HHS · GM 59170 · United States
External Links
PubMed source DOI: 10.1128/MCB.23.7.2341-2350.2003 PMC Full Text View journal details
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