Abstract
The cytotoxic T lymphocyte protease granzyme A induces caspase-independent cell death in which DNA single-strand nicking is observed instead of oligonucleosomal fragmentation. Granzyme A is a specific tryptase that concentrates in the nucleus of targeted cells and synergistically enhances DNA fragmentation induced by the caspase activator granzyme B. Here we show that granzyme A treatment of isolated nuclei enhances DNA accessibility to exogenous endonucleases. In vitro and after cell loading with perforin, GrnA completely degrades histone H1 and cleaves core histones into approximately 16-kDa fragments. Histone digestion provides a mechanism for unfolding compacted chromatin and facilitating endogenous DNase access to DNA during T cell and natural killer cell granule-mediated apoptosis.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Bacterial Proteins / metabolism
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COS Cells
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Caspase Inhibitors
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Caspases / metabolism
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Cell Nucleus / metabolism
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Chromatin / metabolism
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DNA / metabolism
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DNA-Binding Proteins / metabolism
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Deoxyribonucleases / metabolism
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Granzymes
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HL-60 Cells
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Heparin / analogs & derivatives
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Heparin / metabolism
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Histones / metabolism*
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Humans
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K562 Cells
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Membrane Glycoproteins / metabolism
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Perforin
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Pore Forming Cytotoxic Proteins
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Protein Structure, Tertiary / physiology
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Proteoglycans / metabolism
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Serine Endopeptidases / metabolism*
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Substrate Specificity
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T-Lymphocytes, Cytotoxic / enzymology*
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T-Lymphocytes, Cytotoxic / metabolism
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Trypsin / metabolism
Substances
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Bacterial Proteins
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Caspase Inhibitors
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Chromatin
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DNA-Binding Proteins
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Histones
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Membrane Glycoproteins
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PHAP protein, Bacteria
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Pore Forming Cytotoxic Proteins
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Proteoglycans
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heparin proteoglycan
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Perforin
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Heparin
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DNA
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Deoxyribonucleases
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Granzymes
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Serine Endopeptidases
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Trypsin
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GZMA protein, human
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Caspases