Journal
SCIENCE
Volume 368, Issue 6486, Pages 46-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aax6367
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Funding
- Canadian Institute of Health Research grant [BMA342854]
- NIH [R35GM130302, F32GM128265]
- Basser Center for BRCA Award
- St. John's University [579-1110-6709]
- Breast Cancer Now [CTR-Q4-Y2]
- Cancer Research UK [CRUK/A14276]
- ALS-ENABLE program - National Institutes of Health [P30 GM124169-01, DE-AC02-05CH11231]
- National Cancer Institute grant Structural Biology of DNA Repair (SBDR) [CA92584]
- Department of Pharmaceutical Sciences
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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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