- Structural basis for allosteric PARP-1 retention on DNA breaks.
Structural basis for allosteric PARP-1 retention on DNA breaks.
Science (New York, N.Y.) (2020-04-04)
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
PMID32241924
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.
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