Positive feedback sharpens the anaphase switch.
At the onset of anaphase, sister-chromatid cohesion is dissolved abruptly and irreversibly, ensuring that all chromosome pairs disjoin almost simultaneously. The regulatory mechanisms that generate this switch-like behaviour are unclear. Anaphase is initiated when a ubiquitin ligase, the anaphase-promoting complex (APC), triggers the destruction of securin, thereby allowing separase, a protease, to disrupt sister-chromatid cohesion. Here we demonstrate that the cyclin-dependent kinase 1 (Cdk1)-dependent phosphorylation of securin near its destruction-box motif inhibits securin ubiquitination by the APC. The phosphatase Cdc14 reverses securin phosphorylation, thereby increasing the rate of securin ubiquitination. Because separase is known to activate Cdc14 (refs 5 and 6), our results support the existence of a positive feedback loop that increases the abruptness of anaphase. Consistent with this model, we show that mutations that disrupt securin phosphoregulation decrease the synchrony of chromosome segregation. Our results also suggest that coupling securin degradation with changes in Cdk1 and Cdc14 activities helps coordinate the initiation of sister-chromatid separation with changes in spindle dynamics.
Holt
Liam J
LJ
Department of Physiology, University of California, San Francisco, California 94158, USA.
Krutchinsky
Andrew N
AN
Morgan
David O
DO
D000705:Anaphase / Q000502:physiology*; D016203:CDC2 Protein Kinase / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D025461:Feedback, Physiological / Q000235:genetics / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000166:cytology* / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism; D064249:Securin; D017384:Sequence Deletion; D008941:Spindle Apparatus / Q000378:metabolism; D054875:Ubiquitination / Q000502:physiology
C074860:CDC14 protein, S cerevisiae; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C578004:PDS1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D064249:Securin; D016203:CDC2 Protein Kinase; D017027:Protein Tyrosine Phosphatases