scholarly journals Induction of Rapid Histone Degradation by the Cytotoxic T Lymphocyte Protease Granzyme A

2000 ◽  
Vol 276 (5) ◽  
pp. 3683-3690 ◽  
Author(s):  
Dong Zhang ◽  
Mark S. Pasternack ◽  
Paul J. Beresford ◽  
Ludwig Wagner ◽  
Arnold H. Greenberg ◽  
...  
Keyword(s):  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Granzyme A

scholarly journals HMG2 Interacts with the Nucleosome Assembly Protein SET and Is a Target of the Cytotoxic T-Lymphocyte Protease Granzyme A

2002 ◽  
Vol 22 (8) ◽  
pp. 2810-2820 ◽  
Author(s):  
Zusen Fan ◽  
Paul J. Beresford ◽  
Dong Zhang ◽  
Judy Lieberman
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Dna Repair ◽  
Dna Binding ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Nucleosome Assembly ◽  
Nucleosome Assembly Protein ◽  
Granzyme A ◽  
Dna Binding And Bending

ABSTRACT The cytotoxic T-lymphocyte protease granzyme A induces caspase-independent cell death in which DNA single-stranded nicking is observed instead of oligonucleosomal fragmentation. A 270- to 420-kDa endoplasmic reticulum-associated complex (SET complex) containing the nucleosome assembly protein SET, the tumor suppressor pp32, and the base excision repair enzyme APE can induce single-stranded DNA damage in isolated nuclei in a granzyme A-dependent manner. The normal functions of the SET complex are unknown, but the functions of its components suggest that it is involved in activating transcription and DNA repair. We now find that the SET complex contains DNA binding and bending activities mediated by the chromatin-associated protein HMG2. HMG2 facilitates assembly of nucleoprotein higher-order structures by bending and looping DNA or by stabilizing underwound DNA. HMG2 is in the SET complex and coprecipitates with SET. By confocal microscopy, it is observed that cytoplasmic HMG2 colocalizes with SET in association with the endoplasmic reticulum, but most nuclear HMG2 is unassociated with SET. This physical association suggests that HMG2 may facilitate the nucleosome assembly, transcriptional activation, and DNA repair functions of SET and/or APE. HMG2, like SET and APE, is a physiologically relevant granzyme A substrate in targeted cells. HMG1, however, is not a substrate. Granzyme A cleavage after Lys65 in the midst of HMG box A destroys HMG2-mediated DNA binding and bending functions. Granzyme A cleavage and functional disruption of key nuclear substrates, including HMG2, SET, APE, lamins, and histones, are likely to cripple the cellular repair response to promote cell death in this novel caspase-independent death pathway.

scholarly journals The cytotoxic T lymphocyte protease granzyme A cleaves and inactivates poly(adenosine 5′-diphosphate-ribose) polymerase-1

Blood ◽  
2009 ◽  
Vol 114 (6) ◽  
pp. 1205-1216 ◽  
Author(s):  
Pengcheng Zhu ◽  
Denis Martinvalet ◽  
Dipanjan Chowdhury ◽  
Dong Zhang ◽  
Ann Schlesinger ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
T Lymphocyte ◽  
Catalytic Domain ◽  
Cytotoxic T Lymphocyte ◽  
Dominant Negative ◽  
Dna Binding Domain ◽  
Granzyme A ◽  
Dying Cells ◽  
Parp 1

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 Lys498 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.

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