| First Author | Zhu P | Year | 2009 |
| Journal | Blood | Volume | 114 |
| Issue | 6 | Pages | 1205-16 |
| PubMed ID | 19506301 | Mgi Jnum | J:151727 |
| Mgi Id | MGI:4355116 | Doi | 10.1182/blood-2008-12-195768 |
| Citation | Zhu P, et al. (2009) The cytotoxic T lymphocyte protease granzyme A cleaves and inactivates poly(adenosine 5'-diphosphate-ribose) polymerase-1. Blood 114(6):1205-16 |
| abstractText | 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. |
