title: Oscillation of APC/C activity during cell cycle arrest promotes centrosome amplification.
abstract: 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.
authors.affiliation: Department of Biochemistry, University of Leicester, Lancaster Road, Leicester LE1 9HN,  UK.
authors.forename: Suzanna L
authors.initials: SL
authors.lastname: Prosser
authors.forename: Mugdha D
authors.initials: MD
authors.lastname: Samant
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Baxter
authors.forename: Ciaran G
authors.initials: CG
authors.lastname: Morrison
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Fry
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002502:Centrioles / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D018385:Centrosome / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D010450:Endopeptidases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000528:radiation effects; D006367:HeLa Cells; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011839:Radiation, Ionizing; D064247:Separase; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects; D008941:Spindle Apparatus / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*; D000097869:Polo-Like Kinase 1
chemical_list: D064173:Anaphase-Promoting Complex-Cyclosome; D018797:Cell Cycle Proteins; D010450:Endopeptidases; D006918:Hydroxyurea; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D064247:Separase; D043743:Ubiquitin-Protein Ligase Complexes; D000097869:Polo-Like Kinase 1; C577987:ESPL1 protein, human