Cleaving the oxidative repair protein Ape1 enhances cell death mediated by granzyme A

10.1038/ni885 ◽  
2003 ◽  
Vol 4 (2) ◽  
pp. 145-153 ◽  
Author(s):  
Zusen Fan ◽  
Paul J. Beresford ◽  
Dong Zhang ◽  
Zhan Xu ◽  
Carl D. Novina ◽  
...  
Keyword(s):  
Cell Death ◽  
Granzyme A ◽  
Repair Protein

scholarly journals Detection of active Granzyme A in NK92 cells with fluorescent activity-based probe

2019 ◽  
Author(s):  
Sonia Kołt ◽  
Tomasz Janiszewski ◽  
Dion Kaiserman ◽  
Sylwia Modrzycka ◽  
Scott J. Snipas ◽  
...  
Keyword(s):  
Cell Death ◽  
Cytotoxic T Lymphocytes ◽  
Serine Proteases ◽  
Effector Cell ◽  
Viral Infections ◽  
Cell Types ◽  
Substrate Specificities ◽  
Multiple Strategies ◽  
Granzyme A ◽  
Wide Range

AbstractCytotoxic T-lymphocytes (CTLs) and natural killer cells (NKs) kill compromised cells to defend against tumor and viral infections. Both effector cell types use multiple strategies to induce target cell death including Fas/CD95 activation; and the release of perforin and a group of lymphocyte granule serine proteases called granzymes. Granzymes have relatively broad and overlapping substrate specificities and may hydrolyze a wide range of peptidic epitopes; it is therefore challenging to identify their natural and synthetic substrates and to distinguish their localization and functions. Here, we present a specific and potent substrate, an inhibitor, and an activity-based probe of Granzyme A (GrA) that can be used to follow functional GrA in cells.

scholarly journals Inhibition of Karyopherin-α2 Augments Radiation-Induced Cell Death by Perturbing BRCA1-Mediated DNA Repair

2019 ◽  
Vol 20 (11) ◽  
pp. 2843 ◽  
Author(s):  
Kyung-Hee Song ◽  
Seung-Youn Jung ◽  
Jeong-In Park ◽  
Jiyeon Ahn ◽  
Jong Kuk Park ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Dna Repair ◽  
Apoptotic Cell ◽  
Nucleocytoplasmic Transport ◽  
Repair Protein ◽  
Damage Response ◽  
Dna Repair Protein ◽  
Radiation Induced ◽  
Early Local Recurrence

Ionizing radiation (IR) has been widely used in the treatment of cancer. Radiation-induced DNA damage triggers the DNA damage response (DDR), which can confer radioresistance and early local recurrence by activating DNA repair pathways. Since karyopherin-α2 (KPNA2), playing an important role in nucleocytoplasmic transport, was significantly increased by IR in our previous study, we aimed to determine the function of KPNA2 with regard to DDR. Exposure to radiation upregulated KPNA2 expression in human colorectal cancer HT29 and HCT116 cells and breast carcinoma MDA-MB-231 cells together with the increased expression of DNA repair protein BRCA1. The knockdown of KPNA2 effectively increased apoptotic cell death via inhibition of BRCA1 nuclear import following IR. Therefore, we propose that KPNA2 is a potential target for overcoming radioresistance via interruption to DDR.

scholarly journals The Exonuclease TREX1 Is in the SET Complex and Acts in Concert with NM23-H1 to Degrade DNA during Granzyme A-Mediated Cell Death

2006 ◽  
Vol 23 (1) ◽  
pp. 133-142 ◽  
Author(s):  
Dipanjan Chowdhury ◽  
Paul J. Beresford ◽  
Pengcheng Zhu ◽  
Dong Zhang ◽  
Jung-Suk Sung ◽  
...  
Keyword(s):  
Cell Death ◽  
Granzyme A ◽  
Exonuclease Trex1

Histone H3 is Digested by Granzyme A During Compromised Cell Death in the Raji Cells

2015 ◽  
Vol 25 (9) ◽  
pp. 1578-1582 ◽  
Author(s):  
Phil Young Lee ◽  
Byoung Chul Park ◽  
Seung Wook Chi ◽  
Kwang-Hee Bae ◽  
Sunhong Kim ◽  
...  
Keyword(s):  
Cell Death ◽  
Histone H3 ◽  
Raji Cells ◽  
Granzyme A

scholarly journals Granzyme A Cleaves a Mitochondrial Complex I Protein to Initiate Caspase-Independent Cell Death

Cell ◽  
2008 ◽  
Vol 133 (4) ◽  
pp. 681-692 ◽  
Author(s):  
Denis Martinvalet ◽  
Derek M. Dykxhoorn ◽  
Roger Ferrini ◽  
Judy Lieberman
Keyword(s):  
Cell Death ◽  
Complex I ◽  
Mitochondrial Complex I ◽  
Mitochondrial Complex ◽  
Granzyme A

scholarly journals New Aspects of HECT-E3 Ligases in Cell Senescence and Cell Death of Plants

Plants ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 483
Author(s):  
Wei Lan ◽  
Ying Miao
Keyword(s):  
Cell Death ◽  
Mammalian Cells ◽  
Cell Senescence ◽  
Research Progress ◽  
E3 Ligases ◽  
Repair Protein ◽  
Dna Repair Protein ◽  
Ubiquitination Pathway ◽  
Redundant Functions ◽  
Structure And Functions

Plant cells undergo massive orderly changes in structure, biochemistry, and gene expression during cell senescence. These changes cannot be distinguished from the hydrolysis/degradation function controlled by the ubiquitination pathway, autophagy, and various hydrolases in cells. In this mini-review, we summarized current research progress that the human HECT (homologous to the E6AP carboxyl terminus)-type ubiquitin E3 ligases have non-redundant functions in regulating specific signaling pathways, involved in a number of human diseases, especially aging-related diseases, through the influence of DNA repair, protein stability, and removal efficiency of damaged proteins or organelles. We further compared HECT E3 ligases’ structure and functions between plant and mammalian cells, and speculated new aspects acting as degrading signals and regulating signals of HECT E3 ligase in cell senescence and the cell death of plants.

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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