ATP modulates poly(ADP-ribose) polymerase-1-facilitated topoisomerase I-linked DNA religation in the presence of camptothecin.
Poly(ADP-ribose) polymerase (PARP)-1 was reported to promote the religation activity of topoisomerase I in the presence of camptothecin by itself through the direct interaction with topoisomerase I or by the formation of poly(ADP-ribosyl)ated topoisomerase I. We have demonstrated previously that ATP inhibited PARP-1/NAD-facilitated religation of topoisomerase I-linked DNA (TLD) in the presence of camptothecin. The mechanism of action was further studied in the present work. ATP as well as other nucleotides, including CTP, UTP, and GTP, had no effect on topoisomerase I cleavage and religation activities in the absence of camptothecin. In the presence of camptothecin or its derivative topotecan, ATP (at up to 2 mM) inhibited PARP-1/NAD-facilitated TLD religation in a dose-dependent manner. This could be due to the suppression of topoisomerase I poly(ADP-ribosyl)ation through the competition with NAD for the binding site(s) on PARP-1. The interaction between ATP and PARP-1 was independent of ATP hydrolysis. Study of different nucleotide analogs revealed that the structure could determine the dose response of nucleotides. In addition, it was noted that higher concentrations of ATP and CTP (at 2.5 mM or higher) promoted DNA religation by a PARP-1-independent mechanism. Our study implies the possible role of ATP and other nucleotides in the regulation of topoisomerase I activity in the presence of camptothecin analogs.
Park
Shin-Young
SY
Department of Pharmacology, Yale University School of Medicine, P.O. Box 208066, New Haven, CT 06520-8066, USA.
Leung
Chung-Hang
CH
Cheng
Yung-Chi
YC
D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002166:Camptothecin / Q000494:pharmacology*; D002460:Cell Line; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D006801:Humans; D007313:Insecta; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D059004:Topoisomerase I Inhibitors
D059004:Topoisomerase I Inhibitors; D000255:Adenosine Triphosphate; D004247:DNA; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin