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Biochemistry. 1998 Mar 17;37(11):3818-23.

Mammalian DNA topoisomerase I activity and poisoning by camptothecin are inhibited by simian virus 40 large T antigen.

Author information

1
Laboratory of Molecular Pharmacology, National Cancer Institute, Bethesda, Maryland 20892-4255, USA. pommier@nih.gov

Abstract

DNA topoisomerase I (top1) is a ubiquitous enzyme that forms reversible DNA single-strand breaks (cleavage complexes) and plays a role in transcription, DNA replication, and repair. Top1 is the target of camptothecins which selectively trap top1 cleavage complexes and represent a novel class of anticancer drugs active against human solid tumors. The present study demonstrates that recombinant large T antigen (T-Ag), a virus encoded helicase with strong affinity for tumor suppressors and cell cycle- and replication-related proteins, suppresses top1 cleavage complexes and top1 catalytic activity. This top1 suppressive activity is probably not due to T-Ag binding to DNA, as a T-Ag truncation mutant containing only the first 246 amino acids and deficient in DNA binding also inhibited top1, and the inhibition was independent of ATP. T-Ag also antagonized and reversed the trapping of top1 cleavage complexes by camptothecin. These results demonstrate a functional interaction between T-Ag and top1: they also suggest the importance of top1-protein interactions for the regulation of DNA replication and modulation of camptothecin activity.

PMID:
9521701
DOI:
10.1021/bi972067d
[Indexed for MEDLINE]

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