title: Minor grove binding ligands disrupt PARP-1 activation pathways.
abstract: PARP-1 is a nuclear enzyme regulating transcription, chromatin restructuring, and DNA repair. PARP-1 is activated by interaction with NAD+, DNA, and core histones. Each route of PARP-1 activation leads to somewhat different outcomes. PARP-1 interactions with core histones control PARP-1 functions during transcriptional activation in euchromatin. DNA-dependent regulation of PARP-1 determines its localization in heterochromatin and PARP-1-dependent silencing. Here we address the biological significance of DNA-dependent PARP-1 regulation in vitro and in vivo. We report that minor grove binding ligands (MGBLs) specifically target PARP-1 interaction with DNA, and, hence, the DNA-dependent pathway of PARP-1 activation. By obstructing its interaction with DNA molecules, MGBLs block PARP-1 activity in vitro and in vivo, as we demonstrate using Drosophila, as well as human cancer-derived cells. We also demonstrate synergistic inhibition of PARP-1, combining MGBLs with conventional NAD+-dependent inhibitors in human cancer cells. These results suggest that combining different classes of PARP-1 inhibitors can precisely modulate PARP-1 activity in living cells, thus holding promise for new avenues of cancer treatment.
authors: Blokhin Cancer Research Center RAMS, Moscow, Russia.
authors: Kirill I
authors: KI
authors: Kirsanov
authors: Elena
authors: E
authors: Kotova
authors: Petr
authors: P
authors: Makhov
authors: Konstantin
authors: K
authors: Golovine
authors: Ekaterina A
authors: EA
authors: Lesovaya
authors: Vladimir M
authors: VM
authors: Kolenko
authors: Marianna G
authors: MG
authors: Yakubovskaya
authors: Alexei V
authors: AV
authors: Tulin
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D002417:Cattle; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004260:DNA Repair; D004330:Drosophila; D005260:Female; D006801:Humans; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D010051:Ovarian Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D008024:Ligands; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D004247:DNA; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases