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Poly(ADP-Ribose) Polymerase-1 Could Facilitate the Religation of Topoisomerase I-linked DNA Inhibited by Camptothecin

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut

Requests for reprints: Yung-Chi Cheng, Department of Pharmacology, Yale University School of Medicine, SHM B226, P.O. Box 208066, New Haven, CT 06520-8066. Phone: 203-785-7119; Fax: 203-785-7129; E-mail: yccheng{at}yale.edu.

Poly(ADP-ribose) polymerase-1 (PARP-1) is known to have an important role in camptothecin sensitivity and interacts with topoisomerase I. In the present study, the impact of PARP-1 on the topoisomerase I-DNA complex stabilized by camptothecin was assessed. It was shown that NH₂ terminus–truncated topoisomerase I (amino acids 201-765) showed at least 4-fold less sensitivity to camptothecin than full-length topoisomerase I in the oligonucleotide religation assay. PARP-1 could prevent the action of camptothecin on the religation activity of full-length topoisomerase I, which is linked to DNA in a stoichiometrical manner. However, the religation activity of NH₂ terminus–truncated topoisomerase I, which is linked to DNA, could not be enhanced by PARP-1 in the presence of camptothecin. Both full-length and NH₂ terminus–truncated topoisomerase I interact with PARP-1. This data suggests that PARP-1 destabilizes the topoisomerase I-camptothecin-DNA complex with the participation of the NH₂-terminal domain of topoisomerase I. Poly(ADP-ribosyl)ation of topoisomerase I by PARP-1 in the presence its substrate, NAD, could also promote the religation activity of full-length topoisomerase I as well as NH₂ terminus–truncated topoisomerase I. PARP-1 inhibitors (3-aminobenzamide, PJ34) could inhibit this process. Therefore, PARP-1 could facilitate the religation activity of topoisomerase I by itself through topoisomerase I-PARP-1 interaction (PARP-1 action) or by the formation of poly(ADP-ribosyl)ation of topoisomerase I (PARP-1/NAD action). This study also implies that PARP-1 and PARP-1/NAD actions need to be highly regulated by cellular factors for camptothecin to exert its cytotoxicity inside the cells. We propose ATP to be one of the important regulatory factors.

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