2. coordination of the cytokinetic machinery with spindle function.

While originally focusing on the dynamics and biophysical properties of septins (Dobbelaere and Barral, Science 2004; John et al., EMBO J., 2007), we came to the realization that the last step of cytokinesis, abscission, was tightly coordinated with chromosome segregation. Indeed, a cell cycle checkpoint, which we called NoCut, delays the completion of abscission in response to spindle elongation defects (Norden et al., Cell, 2006). We show that the yeast aurora kinase, Ipl1, is part of a chromatin sensor on the spindle midzone (Norden et al., Cell, 2006; Mendoza et al., 2009) that triggers two proteins, Boi1 and Boi2, to translocate to the cell cortex at the site of cleavage in response to lagging chromatin. At the site of cleavage, Boi1 and Boi2 act as abscission inhibitors.

To determine what the actual mechanism of abscission is and how NoCut inhibits it, we currently use genetics to characterize the abscission machinery. These screens identified 105 genes as being required for abscission. However, only 10-15 of them encode actual components of the abscission machinery. We also characterize the signal transduction machinery that controls Boi1 and Boi2 localization in response to aurora activation, and the physiological condition in which NoCut becomes important for cellular viability. Remarkably, some evidences suggest that NoCut is conserved in human, where it plays an important role in preventing tetraploidisation (Steigemann et al., 2009). Therefore, we are convinced that the NoCut checkpoint will be found to play an important role in preventing cancer.

(A) During early anaphase, surrounding chromatin activates Ipl1 at the central spindle, where Ipl1 localizes. Active Ipl1 causes
Boi1 and Boi2 to translocate to the cortex, where they inhibit abscission.
(B) Upon segregation of the chromosomes away from the central spindle, Ipl1 is no longer kept active by chromatin. Boi1 and
Boi2 leave the bud neck. Abscission can take place.
(C) In cells with midzone defects, Ipl1 stays close to chromatin even after chromosome segregation. Boi1 and Boi2 are not
removed from the bud neck. Abscission remains inhibited.