The cytotoxic T lymphocyte protease granzyme A cleaves and inactivates poly(adenosine 5'-diphosphate-ribose) polymerase-1.
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.
Zhu
Pengcheng
P
Immune Disease Institute and Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Martinvalet
Denis
D
Chowdhury
Dipanjan
D
Zhang
Dong
D
Schlesinger
Ann
A
Lieberman
Judy
J
D019943:Amino Acid Substitution; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology / Q000276:immunology*; D020169:Caspases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004249:DNA Damage / Q000276:immunology*; D004260:DNA Repair / Q000235:genetics / Q000276:immunology*; D015870:Gene Expression; D053804:Granzymes / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D020014:K562 Cells; D020125:Mutation, Missense; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology
C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D053804:Granzymes; D020169:Caspases