Mediation of Poly(ADP-Ribose) Polymerase-1-Dependent Cell Death by Apoptosis-Inducing Factor
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Abstract
Poly(ADP-ribose) polymerase-1 (PARP-1) protects the genome by functioning in the DNA damage surveillance network. PARP-1 is also a mediator of cell death after ischemia-reperfusion injury, glutamate excitotoxicity, and various inflammatory processes. We show that PARP-1 activation is required for translocation of apoptosis-inducing factor (AIF) from the mitochondria to the nucleus and that AIF is necessary for PARP-1-dependent cell death. N-methyl-N'-nitro-N-nitrosoguanidine, H2O2, and N-methyl-d-aspartate induce AIF translocation and cell death, which is prevented by PARP inhibitors or genetic knockout of PARP-1, but is caspase independent. Microinjection of an antibody to AIF protects against PARP-1-dependent cytotoxicity. These data support a model in which PARP-1 activation signals AIF release from mitochondria, resulting in a caspase-independent pathway of programmed cell death.
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The record
- Venue
- Science
- Topic
- PARP inhibition in cancer therapy
- Field
- Medicine
- Canadian institutions
- Université Laval
- Funders
- —
- Keywords
- Poly ADP ribose polymeraseApoptosis-inducing factorProgrammed cell deathApoptosisMitochondrionCell biologyCaspaseBiologyMolecular biologyPolymeraseChemistryBiochemistryDNA
- Has abstract in OpenAlex
- yes