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The Hidden Rhythms of the Dividing Cell
The cell divides in a series of discrete steps that occur in a specific order. Lu and Cross (2010) now propose that cell-cycle events are ordered by a regulatory system in which a master oscillator, based on cyclin-dependent kinases, entrains a series of peripheral oscillators controlling individual events
Sequential primed kinases create a damage-responsive phosphodegron on Eco1.
Sister-chromatid cohesion is established during S phase when Eco1 acetylates cohesin. In budding yeast, Eco1 activity falls after S phase due to Cdk1-dependent phosphorylation, which triggers ubiquitination by SCF(Cdc4). We show here that Eco1 degradation requires the sequential actions of Cdk1 and two additional kinases, Cdc7-Dbf4 and the GSK-3 homolog Mck1. These kinases recognize motifs primed by previous phosphorylation, resulting in an ordered sequence of three phosphorylation events on Eco1. Only the latter two phosphorylation sites are spaced correctly to bind Cdc4, resulting in strict discrimination between phosphates added by Cdk1 and by Cdc7. Inhibition of Cdc7 by the DNA damage response prevents Eco1 destruction, allowing establishment of cohesion after S phase. This elaborate regulatory system, involving three independent kinases and stringent substrate selection by a ubiquitin ligase, enables robust control of cohesion establishment during normal growth and after stress
Separase Biosensor Reveals that Cohesin Cleavage Timing Depends on Phosphatase PP2ACdc55 Regulation
SummaryIn anaphase, sister chromatids separate abruptly and are then segregated by the mitotic spindle. The protease separase triggers sister separation by cleaving the Scc1/Mcd1 subunit of the cohesin ring that holds sisters together. Polo-kinase phosphorylation of Scc1 promotes its cleavage, but the underlying regulatory circuits are unclear. We developed a separase biosensor in Saccharomyces cerevisiae that provides a quantitative indicator of cohesin cleavage in single cells. Separase is abruptly activated and cleaves most cohesin within 1Ā min, after which anaphase begins. Cohesin near centromeres and telomeres is cleaved at the same rate and time. Protein phosphatase PP2ACdc55 inhibits cohesin cleavage by counteracting polo-kinase phosphorylation of Scc1. In early anaphase, the previously described separase inhibition of PP2ACdc55 promotes cohesin cleavage. Thus, separase acts directly on Scc1 and also indirectly, through inhibition of PP2ACdc55, to stimulate cohesin cleavage, providing a feedforward loop that may contribute to a robust and timely anaphase
Native Defects and their Doping Response in the Lithium Solid Electrolyte Li<sub>7</sub>La<sub>3</sub>Zr<sub>2</sub>O<sub>12</sub>
py-sc-fermi: self-consistent Fermi energies and defect concentrations from electronic structure calculations
py-sc-fermi: self-consistent Fermi energies and defect concentrations from electronic structure calculations
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Cohesin cleavage by separase is enhanced by a substrate motif distinct from the cleavage site.
Chromosome segregation begins when the cysteine protease, separase, cleaves the Scc1 subunit of cohesin at the metaphase-to-anaphase transition. Separase is inhibited prior to metaphase by the tightly bound securin protein, which contains a pseudosubstrate motif that blocks the separase active site. To investigate separase substrate specificity and regulation, here we develop a system for producing recombinant, securin-free human separase. Using this enzyme, we identify an LPE motif on the Scc1 substrate that is distinct from the cleavage site and is required for rapid and specific substrate cleavage. Securin also contains a conserved LPE motif, and we provide evidence that this sequence blocks separase engagement of the Scc1 LPE motif. Our results suggest that rapid cohesin cleavage by separase requires a substrate docking interaction outside the active site. This interaction is blocked by securin, providing a second mechanism by which securin inhibits cohesin cleavage
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