Journal
BLOOD
Volume 114, Issue 6, Pages 1205-1216Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2008-12-195768
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Funding
- National Institutes of Health [AI-45587]
- Leukemia & Lymphoma Society fellowship
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Granzyme A(GzmA) in killer cells induces caspase-independent programmed cell death. In this study, we show that GzmA cleaves the DNA damage sensor poly( adenosine 5'-diphosphate-ribose) polymerase-1 (PARP-1) after Lys(498) in its automodification domain, separating the DNA binding domain from the catalytic domain, which interferes with repair of GzmA-induced DNA damage and enhances susceptibility to GzmA-mediated death. Overexpressing K498A PARP-1 reduces GzmA-mediated death and drives dying cells to necrosis rather than apoptosis. Conversely, inhibiting or genetically disrupting PARP-1 enhances cell vulnerability. The N-terminal GzmA cleavage fragment of PARP-1 acts as a PARP-1 dominant negative, binding to DNA and blocking DNA repair. Disrupting PARP-1, which is also a caspase target, is therefore required for efficient apoptosis by both caspase-independent and caspase-dependent pathways. (Blood. 2009; 114: 1205-1216)
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