1. Granzyme M targets topoisomerase II alpha to trigger cell cycle arrest and caspase-dependent apoptosis
- Author
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L. I. van der Wal, Kim Plasman, Andrew C.G. Porter, Ka Wai Lai, Kris Gevaert, S A H de Poot, Niels Bovenschen, and P. Van Damme
- Subjects
Programmed cell death ,Cell cycle checkpoint ,Apoptosis ,Caspase-Dependent Apoptosis ,Granzymes ,03 medical and health sciences ,0302 clinical medicine ,Antigens, Neoplasm ,Chlorocebus aethiops ,Tumor Cells, Cultured ,Cytotoxic T cell ,Animals ,Humans ,Molecular Biology ,Caspase ,030304 developmental biology ,0303 health sciences ,Original Paper ,biology ,Cell Death ,Cell Biology ,Cell Cycle Checkpoints ,Cell biology ,DNA-Binding Proteins ,Killer Cells, Natural ,DNA Topoisomerases, Type II ,Granzyme ,030220 oncology & carcinogenesis ,Caspases ,COS Cells ,biology.protein ,Granzyme M ,HeLa Cells - Abstract
Cytotoxic lymphocyte protease granzyme M (GrM) is a potent inducer of tumor cell death. The apoptotic phenotype and mechanism by which it induces cell death, however, remain poorly understood and controversial. Here, we show that GrM-induced cell death was largely caspase-dependent with various hallmarks of classical apoptosis, coinciding with caspase-independent G2/M cell cycle arrest. Using positional proteomics in human tumor cells, we identified the nuclear enzyme topoisomerase II alpha (topoIIα) as a physiological substrate of GrM. Cleavage of topoIIα by GrM at Leu(1280) separated topoIIα functional domains from the nuclear localization signals, leading to nuclear exit of topoIIα catalytic activity, thereby rendering it nonfunctional. Similar to the apoptotic phenotype of GrM, topoIIα depletion in tumor cells led to cell cycle arrest in G2/M, mitochondrial perturbations, caspase activation, and apoptosis. We conclude that cytotoxic lymphocyte protease GrM targets topoIIα to trigger cell cycle arrest and caspase-dependent apoptosis.
- Published
- 2013
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