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Title

The cytotoxic T lymphocyte protease granzyme A cleaves and inactivates poly(adenosine 5'-diphosphate-ribose) polymerase-1

Authors
Zhu, Pengcheng
Chowdhury, Dipanjan
Zhang, Dong
Schlesinger, Ann
Lieberman, Judy
Published in Blood. 2009, vol. 114, no. 6, p. 1205-1216
Abstract 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.
Keywords Amino Acid SubstitutionApoptosis/genetics/*immunologyCD8-Positive T-Lymphocytes/enzymology/*immunologyCaspases/genetics/immunology/metabolismDNA Damage/*immunologyDNA Repair/genetics/*immunologyGene ExpressionGranzymes/genetics/*immunology/metabolismHeLa CellsHumansK562 CellsMutation, MissensePoly(ADP-ribose) Polymerases/genetics/*immunology/metabolismProtein Structure, Tertiary/physiology
Identifiers
PMID: 19506301
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Research group ROS in CTL mediated cell death : from mechanism to applications (898)
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(ISO format)
ZHU, Pengcheng et al. The cytotoxic T lymphocyte protease granzyme A cleaves and inactivates poly(adenosine 5'-diphosphate-ribose) polymerase-1. In: Blood, 2009, vol. 114, n° 6, p. 1205-1216. https://archive-ouverte.unige.ch/unige:19613

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Deposited on : 2012-04-23

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