title: Cohesion fatigue explains why pharmacological inhibition of the APC/C induces a spindle checkpoint-dependent mitotic arrest.
abstract: The Spindle Assembly Checkpoint (SAC) delays the onset of anaphase in response to unattached kinetochores by inhibiting the activity of the Anaphase-Promoting Complex/Cyclosome (APC/C), an E3 ubiquitin ligase. Once all the chromosomes have bioriented, SAC signalling is somehow silenced, which allows progression through mitosis. Recent studies suggest that the APC/C itself participates in SAC silencing by targeting an unknown factor for proteolytic degradation. Key evidence in favour of this model comes from the use of proTAME, a small molecule inhibitor of the APC/C. In cells, proTAME causes a mitotic arrest that is SAC-dependent. Even though this observation comes at odds with the current view that the APC/C acts downstream of the SAC, it was nonetheless argued that these results revealed a role for APC/C activity in SAC silencing. However, we show here that the mitotic arrest induced by proTAME is due to the induction of cohesion fatigue, a phenotype that is caused by the loss of sister chromatid cohesion following a prolonged metaphase. Under these conditions, the SAC is re-activated and APC/C inhibition is maintained independently of proTAME. Therefore, these results provide a simpler explanation for why the proTAME-induced mitotic arrest is also dependent on the SAC. While these observations question the notion that the APC/C is required for SAC silencing, we nevertheless show that APC/C activity does partially contribute to its own release from inhibitory complexes, and importantly, this does not depend on proteasome-mediated degradation.
authors.affiliation: Faculty of Life Sciences, University of Manchester, Manchester, UK.
authors.forename: Pablo
authors.initials: P
authors.lastname: Lara-Gonzalez
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Taylor
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D020090:Chromosome Segregation / Q000235:genetics; D002875:Chromosomes / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D018386:Kinetochores / Q000378:metabolism; D008677:Metaphase / Q000235:genetics; D008938:Mitosis / Q000187:drug effects / Q000235:genetics*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D008941:Spindle Apparatus / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D014106:Tosylarginine Methyl Ester / Q000494:pharmacology*; D043743:Ubiquitin-Protein Ligase Complexes / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D014106:Tosylarginine Methyl Ester; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome; D046988:Proteasome Endopeptidase Complex