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Kirsanov KI , Kotova E , Makhov P , Golovine K , Lesovaya EA , Kolenko VM , Yakubovskaya MG , Tulin AV
Minor grove binding ligands disrupt PARP-1 activation pathways
Oncotarget. 2014 Jan 30;5(2) :428-37
PMID: 24504413 PMCID: PMC3964218 URL: https://www.ncbi.nlm.nih.gov/pubmed/24504413
AbstractPARP-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.
NotesKirsanov, Kirill I Kotova, Elena Makhov, Petr Golovine, Konstantin Lesovaya, Ekaterina A Kolenko, Vladimir M Yakubovskaya, Marianna G Tulin, Alexei V eng R01 DK082623/DK/NIDDK NIH HHS/ R01 GM077452/GM/NIGMS NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Oncotarget. 2014 Jan 30;5(2):428-37. doi: 10.18632/oncotarget.1742.