Granzyme M targets topoisomerase II alpha to trigger cell cycle arrest and caspase-dependent apoptosis.

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 (topoII?) as a physiological substrate of GrM. Cleavage of topoII? by GrM at Leu(1280) separated topoII? functional domains from the nuclear localization signals, leading to nuclear exit of topoII? catalytic activity, thereby rendering it nonfunctional. Similar to the apoptotic phenotype of GrM, topoII? 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 topoII? to trigger cell cycle arrest and caspase-dependent apoptosis.

SUBMITTER: de Poot SA 

PROVIDER: S-EPMC3921589 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature