Structural basis for allosteric PARP-1 retention on DNA breaks
Levani Zandarashvili, Marie-France Langelier, Uday Kiran Velagapudi, Mark A. Hancock, Jamin D. Steffen, Ramya Billur, Zain M. Hannan, Andrew J. Wicks, Dragomir B. Krastev, Stephen J. Pettitt, Christopher J. Lord, Tanaji T. Talele, John M. Pascal, Ben E. Black
Abstract
The success of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors (PARPi) to treat cancer relates to their ability to trap PARP-1 at the site of a DNA break. Although different forms of PARPi all target the catalytic center of the enzyme, they have variable abilities to trap PARP-1. We found that several structurally distinct PARPi drive PARP-1 allostery to promote release from a DNA break. Other inhibitors drive allostery to retain PARP-1 on a DNA break. Further, we generated a new PARPi compound, converting an allosteric pro-release compound to a pro-retention compound and increasing its ability to kill cancer cells. These developments are pertinent to clinical applications where PARP-1 trapping is either desirable or undesirable.