Inhibition of poly(ADP-ribose) polymerase activity affects its subcellular localization and DNA strand break rejoining.
Poly(ADP-ribose) polymerase (PARP) plays a crucial role in DNA repair. Modulation of its activity by stimulation or inhibition is considered as a potentially important strategy in clinical practice, especially to sensitize tumor cells to chemo- and radiotherapy through inhibition of DNA repair. Here we studied the effect of the three PARP inhibitors, 5-iodo-6-amino-benzopyrone (INH(2)BP), 1,5-isoquinolinediol (1,5-dihydroxyisoquinolinediol (1,5-IQD) and 8-hydroxy-2-methylquinazolin-4-[3H]one (NU1025), and for two of them the efficiency in slowing the rejoining of DNA strand breaks induced by H(2)O(2) was compared. Inhibition of PARP changed its intranuclear localization markedly; cells exposed to the inhibitor NU1025 showed a significant tendency to accumulate PARP in large foci, whereas in untreated cells its distribution was more uniform. The speed and efficiency of rejoining of H(2)O(2)-induced DNA strand breaks were lower in cells incubated with a PARP inhibitor, and the kinetics of rejoining were modulated in a different manner by each inhibitor. At a concentration of 100 microM the efficiency of the inhibitors could be ranked in the order NU1025 > IQD > INH(2)BP. The two first compounds were able to decrease the overall PARP activity below the level detected in control cells, while INH(2)BP showed up to 40% PARP activity after exposure to H(2)O(2).
Ryabokon
Nadezhda I
NI
Department of Experimental and Clinical Radiobiology, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland.
Cieślar-Pobuda
Artur
A
Rzeszowska-Wolny
Joanna
J
D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D003374:Coumarins / Q000494:pharmacology*; D053960:DNA Breaks; D004260:DNA Repair / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007546:Isoquinolines; D020014:K562 Cells; D007700:Kinetics; D008856:Microscopy, Fluorescence; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D021381:Protein Transport; D011799:Quinazolines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology
D003374:Coumarins; D004791:Enzyme Inhibitors; D007546:Isoquinolines; C115774:NU 1025; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines; D011804:Quinolines; C071383:5-iodo-6-amino-1,2-benzopyrone; C095653:1,5-dihydroxyisoquinoline; D011065:Poly(ADP-ribose) Polymerases