Final Report Summary - LONGCHROM (Chromosome Segregation and Aneuploidy)
We found that yeast chromosomes increase their compaction in anaphase in a length-dependent manner. This ensures that no chromosome is too long to be properly partitioned to the daughter cell before cytokinesis. The compaction process depends on Aurora B kinase activity at the spindle midzone, and phosphorylation of the chromosome component histone H3. This revealed that chromosome length and mitotic chromosome compaction are intimately linked, allowing the anaphase spindle to function as a ruler to adapt the compaction of chromatids, promoting their removal away from the cytokinesis site, regardless of spindle or DNA length (Neurohr et al., Science 2011).
We then demonstrated that chromosome length is the critical feature determining the time of chromosome disentanglements known as "catenations". Indeed, linear DNA molecules become entangled after replication, and they must be disentangled if they are to be partitioned to the daughter cells before cytokinesis. We found that disentanglement occurs during anaphase as chromosomes are "unzipped" while being pulled to opposite poles of the dividing cell. Disentanglement depends on chromosome length, with longer chromosomes taking longer than shorter ones, and requires the enzyme Topoisomerase II and dynamic microtubules (Titos et al., J Cell Biol 2014). Therefore, cells are able to adjust both chromosome compaction and decatenation during anaphase, to ensure that chromosomes are properly segregated to daughter cells.
Finally, we investigated what happens if compaction and disentanglement processes are not completed when cytokinesis starts. We established that defects in DNA disentanglement, chromatin compaction, and DNA replication cause inhibition of cytokinesis. This is regulated by the Aurora-B-dependent abscission checkpoint, known as NoCut. Our data demonstrate that a key function of the NoCut checkpoint is to provide time for the resolution of chromosome segregation defects, preventing DNA damage during cytokinesis and ensuring genome stability after replicative stress (Amaral et al., Nat Cell Biol 2016).