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Molecular and Cellular Biology, April 2003, p. 2341-2350, Vol. 23, No. 7
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.7.2341-2350.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Transcription-Dependent Degradation of Topoisomerase I-DNA Covalent Complexes

Shyamal D. Desai,1 Hui Zhang,2 Alexandra Rodriguez-Bauman,1 Jin-Ming Yang,3 Xiaohua Wu,3 Murugesan K. Gounder,3 Eric H. Rubin,3 and Leroy F. Liu1*

Department of Pharmacology, UMDNJ-Robert Wood Johnson Medical School, Piscataway, New Jersey 08854,1 Department of Genetics, Yale University, New Haven, Connecticut 06520,2 Department of Medicine and Pharmacology, The Cancer Institute of New Jersey, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey 089013

Received 24 October 2002/ Returned for modification 14 December 2002/ Accepted 7 January 2003

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.

* Corresponding author. Mailing address: Department of Pharmacology, UMDNJ-Robert Wood Johnson Medical School, 675 Hoes La., Piscataway, NJ 08854. Phone: (732) 235-4592. Fax: (732) 235-4073. E-mail: lliu{at}umdnj.edu.

Molecular and Cellular Biology, April 2003, p. 2341-2350, Vol. 23, No. 7
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.7.2341-2350.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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