Induction of rapid histone degradation by the cytotoxic T lymphocyte protease granzyme A

The cytotoxic T lymphocyte protease granzyme A induces caspase-independent cell death in which DNA single-strand nicking is observed instead of oligon ucleosomal fragmentation. Granzyme A is a specific tryptase that concentrat es in the nucleus of targeted cells and synergistically enhances DNA fragme ntation induced by the caspase activator granzyme B. Here we show that gran zyme A treatment of isolated nuclei enhances DNA accessibility to exogenous endonucleases. In vitro and after cell loading with perforin, GrnA complet ely degrades histone H1 and cleaves core histones into similar to 16kDa fra gments. Histone digestion provides a mechanism for unfolding compacted chro matin and facilitating endogenous DNase access to DNA during T cell and nat ural killer cell granule-mediated apoptosis.