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

S.A.H. de Poot, K.W. Lai, L van der Wal, K. Plasman, P. van Damme, A.C. Porter, K. Gevaert, N. Bovenschen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

6 Citations (Scopus)

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. © 2014 Macmillan Publishers Limited All rights reserved.

Original languageEnglish
Pages (from-to)416-426
Number of pages11
JournalCell Death and Differentiation
Volume21
Issue number3
DOIs
Publication statusPublished - Mar 2014

Keywords

  • apoptosis
  • cell cycle arrest
  • granzyme M
  • protease
  • topoisomerase II alpha

Fingerprint

Dive into the research topics of 'Granzyme M targets topoisomerase II alpha to trigger cell cycle arrest and caspase-dependent apoptosis'. Together they form a unique fingerprint.

Cite this