Oncotarget

Research Papers:

Minor grove binding ligands disrupt PARP-1 activation pathways

Kirill Kirsanov, Elena Kotova, Petr Makhov, Konstantin Golovine, Ekaterina A. Lesovaya, Vladimir M. Kolenko, Marianna G. Yakubovskaya, Alexei V. Tulin _

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Oncotarget. 2014; 5:428-437. https://doi.org/10.18632/oncotarget.1742

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Abstract

Kirill I. Kirsanov1,*, Elena Kotova2,*, Petr Makhov2, Konstantin Golovine2, Ekaterina A. Lesovaya1, Vladimir M. Kolenko2, Marianna G. Yakubovskaya1, Alexei V. Tulin2

1 Blokhin Cancer Research Center RAMS, Moscow, Russia

2 Fox Chase Cancer Center, Philadelphia, PA

* These authors contributed equally to this work

Correspondence:

Alexei V. Tulin, email:

Keywords: PARP-1, PARP-1 inhibitors, DNA-binding small molecules, poly(ADP-ribose)

Received: December 25, 2013 Accepted: January 3, 2014 Published: January 3, 2014

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.


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