Oscillation of APC/C activity during cell cycle arrest promotes centrosome amplification
journal contributionposted on 07.03.2014, 12:05 by Suzanna L. Prosser, Mugdha D. Samant, Joanne E. Baxter, Ciaran G. Morrison, Andrew M. Fry
Centrosome duplication is licensed by the disengagement, or ‘uncoupling’, of centrioles during late mitosis. However, arrest of cells in G2 can trigger premature centriole disengagement. Here, we show that premature disengagement results from untimely activation of the anaphase-promoting complex (APC/C), leading to securin degradation and release of active separase. Although APC/C activation during G2 arrest is dependent on polo-like kinase 1 (Plk1)-mediated degradation of the APC/C inhibitor, early mitotic inhibitor 1 (Emi1), Plk1 also has a second APC/C-independent role in promoting disengagement. Importantly, APC/C and Plk1 activity also stimulates centriole disengagement in response to hydroxyurea or DNA damage-induced cell-cycle arrest and this leads to centrosome amplification. However, the reduplication of disengaged centrioles is dependent on cyclin-dependent kinase 2 (Cdk2) activity and Cdk2 activation coincides with a subsequent inactivation of the APC/C and re-accumulation of cyclin A. Although release from these arrests leads to mitotic entry, the presence of disengaged and/or amplified centrosomes results in the formation of abnormal mitotic spindles that lead to chromosome mis-segregation. Thus, oscillation of APC/C activity during cell cycle arrest promotes both centrosome amplification and genome instability.
This work was supported by Cancer Research UK (to A.M.F.); The Wellcome Trust (to A.M.F.); the Association for International Cancer Research (to A.M.F.); and a Science Foundation Ireland Principal Investigator Award [grant number 10/IN.1/B2972 to C.G.M.
CitationJournal of Cell Science, 2012, 125 (22), pp. 5353–5368
Author affiliation/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Biological Sciences/Department of Biochemistry
VersionVoR (Version of Record)
Published inJournal of Cell Science
PublisherThe Company of Biologists Ltd
Anaphase-Promoting Complex-CyclosomeCell Cycle CheckpointsCell Cycle ProteinsCentriolesCentrosomeEndopeptidasesEnzyme ActivationHeLa CellsHumansHydroxyureaProtein-Serine-Threonine KinasesProto-Oncogene ProteinsRadiation, IonizingSeparaseSignal TransductionSpindle ApparatusUbiquitin-Protein Ligase Complexes