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Molecular basis of chromosome segregation

Andrea Musacchio


Andrea Musacchio
c/o IFOM-IEO Campus
Via Adamello, 16 - 20139 Milan, Italy
Tel. +39 02 57489829 - +39 02 57489871
Fax +39 0294375990

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fig 1 Key steps in the regulation of mitotic progression

fig 1

After replication, the two copies of the genome are held together by complexes of proteins known as cohesins. In higher eukaryotes, cohesin is first removed from chromosome arms. Residual cohesion at the centromere region is enough to prevent sister-chromatid separation. At the onset of anaphase, these complexes must be disrupted through the proteolytic cleavage of a cohesin subunit (Scc1). This is carried out by a caspase-related activity known as separase. The timing of separase action is the key control point for the onset of anaphase, so how is this regulated? Perhaps the major mode of regulation is that, for most of the cell cycle, separase is inhibited through direct association with a protein called securin. Securin levels are themselves regulated by proteolysis. Securin destruction is carried out by the proteasome and is therefore ubiquitin mediated. Polyubiquitin chains are added to securin by an E3 ubiquitin ligase known as the anaphase-promoting complex or cyclosome (APC). An accessory factor, typically known as Cdc20, is required for this and is a key target of the spindle checkpoint6, 7.

In addition, Scc1 only becomes a good substrate for separase-dependent cleavage once it has been phosphorylated by Polo kinase. An additional pathway regulates separase activity - it must be phosphorylated, probably directly by cyclin-dependent kinases, before it can efficiently cleave cohesin. Whether this is also regulated by a checkpoint remains to be shown. An important regulatory mechanism is provided by the spindle checkpoint. During prometaphase, unattached kinetochores are believed to generate a 'wait anaphase' signal that results in the formation of Cdc20 complexes with Mad2 and BubR1-Bub3. A single quaternary complex containing Mad2, BubR1-Bub3 and Cdc20 might be formed. The interaction of Mad2 and BubR1-Bub3 with Cdc20 prevents the APC from ubiquitylating securin, thus ultimately preventing the activation of separase and loss of cohesion. The attainment of bipolar attachment at metaphase extinguishes the 'wait anaphase' signal, triggering the attachment of polyubiquitin chains onto securin. This leads to separase activation, proteolytic degradation of cohesin and, finally, to anaphase.

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