Granzyme A, which causes single-stranded DNA damage, targets the double-strand break repair protein Ku70.
Granzyme A (GzmA) induces caspase-independent cell death with morphological features of apoptosis. Here, we show that GzmA at nanomolar concentrations cleaves Ku70, a key double-strand break repair (DSBR) protein, in target cells. Ku70 is cut after Arg(301), disrupting Ku complex binding to DNA. Cleaving Ku70 facilitates GzmA-mediated cell death, as ... silencing Ku70 by RNA interference increases DNA damage and cell death by GzmB cluster-deficient cytotoxic T lymphocytes or by GzmA and perforin, whereas Ku70 overexpression has the opposite effect. Ku70 has two known antiapoptotic effects-facilitating DSBR and sequestering bax to prevent its translocation to mitochondria. However, GzmA triggers single-stranded, not double-stranded, DNA damage, and GzmA-induced cell death does not involve bax. Therefore, Ku70 has other antiapoptotic functions in GzmA-induced cell death, which are blocked when GzmA proteolyses Ku70.
Mesh Terms:
Animals, Antigens, Nuclear, Arginine, Cell Nucleus, Cells, Cultured, DNA, DNA Damage, DNA Repair, DNA-Binding Proteins, Gene Expression Regulation, Granzymes, Humans, Membrane Glycoproteins, Mice, Perforin, Pore Forming Cytotoxic Proteins, Protease Inhibitors, Protein Binding, Serine Endopeptidases, T-Lymphocytes, Cytotoxic
Animals, Antigens, Nuclear, Arginine, Cell Nucleus, Cells, Cultured, DNA, DNA Damage, DNA Repair, DNA-Binding Proteins, Gene Expression Regulation, Granzymes, Humans, Membrane Glycoproteins, Mice, Perforin, Pore Forming Cytotoxic Proteins, Protease Inhibitors, Protein Binding, Serine Endopeptidases, T-Lymphocytes, Cytotoxic
EMBO Rep.
Date: Apr. 01, 2006
PubMed ID: 16440001
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