The cytotoxic T lymphocyte protease granzyme A cleaves and inactivates poly(adenosine 5'-diphosphate-ribose) polymerase-1.
نویسندگان
چکیده
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.
منابع مشابه
Biol. Pharm. Bull. 30(4) 655—660 (2007)
netically controlled mechanism by which multicellular organisms to regulate normal cell development, tissue homeostasis, and immunological responses. During apoptosis, various cellular events occur, including morphological changes, exposure of phosphatidylserine (PS) on the cell surface, and fragmentation of nuclei. Molecules on the surfaces of apoptotic cells are recognized by macrophages and ...
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عنوان ژورنال:
- Blood
دوره 114 6 شماره
صفحات -
تاریخ انتشار 2009