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Structural basis for allosteric PARP-1 retention on DNA breaks.

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.

SUBMITTER: Zandarashvili L

PROVIDER: S-EPMC7347020 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Structural basis for allosteric PARP-1 retention on DNA breaks.

Zandarashvili Levani L Langelier Marie-France MF Velagapudi Uday Kiran UK Hancock Mark A MA Steffen Jamin D JD Billur Ramya R Hannan Zain M ZM Wicks Andrew J AJ Krastev Dragomir B DB Pettitt Stephen J SJ Lord Christopher J CJ Talele Tanaji T TT Pascal John M JM Black Ben E BE

Science (New York, N.Y.) 20200401 6486

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 compoun ...[more]

PMID: 32241924

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