See also: LL Fava & A Villunger (September 2014)
Genome-wide siRNA screen reveals coupling between mitotic apoptosis and adaptation
Article first published online: 14 JUL 2014
© 2014 The Authors
The EMBO Journal
Volume 33, Issue 17, pages 1960–1976, 1 September 2014
How to Cite
The EMBO Journal (2014) 33: 1960–1976
- Issue published online: 1 SEP 2014
- Article first published online: 14 JUL 2014
- Manuscript Accepted: 18 JUN 2014
- Manuscript Revised: 23 MAY 2014
- Manuscript Received: 3 JAN 2014
- Research Supplement to Promote Diversity in the Health Sciences. Grant Number: R01CA125269
- Welch Foundation. Grant Number: I-1441
- Cancer Prevention and Research Institute of Texas. Grant Numbers: RP110465-P3, RP120717-P2
- mitotic slippage;
- the spindle checkpoint
The antimitotic anti-cancer drugs, including taxol, perturb spindle dynamics, and induce prolonged, spindle checkpoint-dependent mitotic arrest in cancer cells. These cells then either undergo apoptosis triggered by the intrinsic mitochondrial pathway or exit mitosis without proper cell division in an adaptation pathway. Using a genome-wide small interfering RNA (siRNA) screen in taxol-treated HeLa cells, we systematically identify components of the mitotic apoptosis and adaptation pathways. We show that the Mad2 inhibitor p31comet actively promotes mitotic adaptation through cyclin B1 degradation and has a minor separate function in suppressing apoptosis. Conversely, the pro-apoptotic Bcl2 family member, Noxa, is a critical initiator of mitotic cell death. Unexpectedly, the upstream components of the mitochondrial apoptosis pathway and the mitochondrial fission protein Drp1 contribute to mitotic adaption. Our results reveal crosstalk between the apoptosis and adaptation pathways during mitotic arrest.
Prolonged mitotic arrest induced by anti-proliferative drugs eventually results in apoptotic cell death or in mitotic exit due to checkpoint adaptation. An RNAi screen in human cancer cells lines offers new insights into the regulatory networks underlying these processes.
- Genome-wide siRNA screen identifies regulators of mitotic cell death and checkpoint adaptation.
- The BH3-only protein Noxa promotes apoptosis during mitotic arrest.
- The spindle checkpoint regulator p31comet suppresses mitotic adaptation and facilitates apoptosis.
- A Bax/Bak mitochondrial module couples mitotic apoptosis and adaptation.
- The mitochondrial fission factor Drp1 promotes mitotic checkpoint adaptation.