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Granzyme B plays a key role in cell-mediated programmed cell death. We previously demonstrated that p53 is a functional determinant in the granzyme B-induced cytotoxic T-lymphocyte response. However, the pathways leading to activation of p53 by granzyme B remain incompletely understood. We now demonstrate that granzyme B-induced DNA damage signaling as revealed by histone H2AX phosphorylation and subsequent activation of the stress kinase CHK2. Confocal microscopy analysis indicates that granzyme B treatment of tumor cells induced an early translocation of endonuclease caspase-activated DNase. DNA microarray-based global transcriptional profiling and RT-PCR indeed revealed genes related to DNA damage. Among these genes, hSMG-1, a genotoxic stress-activated protein, was constantly upregulated in tumor cells following granzyme B treatment. Knockdown of the hSMG-1 gene in T1 tumor target cell line resulted in a significant inhibition of granzyme B- and CTL-induced killing. Our data suggest that granzyme B may exert cell death through DNA damage signaling and uncover a novel molecular link between the DNA damage pathway and granzyme B-induced cell death. [ABSTRACT FROM AUTHOR]