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

摘要

Granzyme A(Gzm A) in killer cells induces caspase-independent programmed cell death. In this study, we show that GzmA cleaves the DNA damage sensor poly(ade-nosine 5'-diphosphate-ribose) polymerase-1 (PARP-1) after Lys~(498) in its automodi-fication 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 apopto-sis. 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.