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Chromosome Segregation and Aneuploidy

Final Report Summary - LONGCHROM (Chromosome Segregation and Aneuploidy)

Living cells have a fascinating ability to generate complex and dynamic internal structures. This property is most evident during cell division: in a very short time (often of the order of a few minutes) cells alter their shape, partition equal copies of their internal components to opposite poles, and constrict in the middle to divide into two seemingly identical halves. These dramatic changes need to be carefully coordinated with each other in space and time. Critically, the cells’ DNA – contained in compacted rod-like structures called chromosomes – must travel to opposite sides of the cell (a process called anaphase) before this splits in two (cytokinesis). Chromosomes are pulled to their destination in daughter cells by filaments known as microtubules, which form the mitotic spindle; after chromosome segregation, microtubule bundles in the middle of the cell form the spindle midzone, which defines the site of cell division. Chromosomes that are delayed in their journey risk being caught by the cell constriction machinery and damaged, potentially leading to severe pathologies such as cancer. We studied control systems that prevent this catastrophic event in a simple experimental system, the yeast Saccharomyces cerevisiae. Key findings made in yeast are then validated in animal cells.

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).