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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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.

Author Information

Kirill Kirsanov
N.N.Blokhin Cancer Research Center

Elena Kotova
Fox Chase Cancer Center

Petr Makhov
Fox Chase Cancer Center

Konstantin Golovine
Fox Chase Cancer Center

Ekaterina A. Lesovaya
N.N.Blokhin Cancer Research Center

Vladimir M. Kolenko
Fox Chase Cancer Center

Marianna G. Yakubovskaya
N.N.Blokhin Cancer Research Center

Alexei V. Tulin
Primary Contact  _

Fox Chase Cancer Center


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