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Chromosome self-clearing completes sister chromatid separation

Final Report Summary - SELFCC (Chromosome self-clearing completes sister chromatid separation)

To maintain genetic integrity, eukaryotic cells must duplicate their chromosomes in high fidelity and correctly segregate duplicated chromosomes to daughter cells when cells divide. This topic has important medical relevance as failure in these processes could cause human diseases characterised by abnormal chromosome numbers and instability. To ensure chromosome segregation, sister chromatid cohesion must hold duplicated chromosomes together, but cohesion must be dissolved efficiently when chromosome segregation starts. In addition, duplicated chromosomes must be efficiently resolved from each other and subsequently compacted, prior to segregation; otherwise chromosomes would stay entangled or excessively long for segregation. In this research program, we studied mechanisms facilitating dissolution of sister chromatid cohesion at anaphase onset, using budding yeast as a model organism. We also studied mechanisms promoting efficient sister chromatid resolution and chromosome compaction in early mitosis of human cells.

In budding yeast, we have found that Smc3 deacetylation by Hos1 plays an important role in facilitating dissolution of sister chromatid cohesion at anaphase onset. Smc3 deacetylation promotes removal of cohesins from chromosomes without changing efficiency of Scc1 cleavage by separase. If Smc3 deacetylation is defective, there is a significant delay in completion of chromosome segregation, and the rate of chromososome missegregation is elevated. Our results suggest that Smc3 deacetylation promotes dissociation of Smc1–Smc3 heads. Scc1 cleavage by separase and subsequent Smc1–3 head dissociation, promoted by Smc3 deacetylation, open up the cohesin ring structure together, which leads to efficient dissolution of sister chromatid cohesion. Our study reveals a novel mechanism facilitating efficient dissolution of cohesion at anaphase onset.

In human cells, we developed a novel assay to quantify progression of sister chromatid resolution and chromosome compaction. We achieved this by analysing changes in configuration of marked chromosome regions over time in live-cell imaging. This assay is unique as we can analyse both sister chromatid resolution and chromosome compaction in a single assay. Using this assay, we can evaluate not only how these two events proceed but also how they are coordinated. Furthermore, this assay evaluates regional changes of chromosome configuration and therefore analyses chromosome dynamics in high spatial resolution. Using this assay, we found important roles of cohesins, topoisomerase II and condensins in sister chromatid resolution and chromosome compaction. For example, local enrichment of cohesins on a chromosome prevents precocious sister chromatid resolution. Condensin II and I play distinct roles in sister chromatid resolution and chromosome compaction, respectively, and our assay quantified their distinct activities in these processes. In conclusion, we discovered novel features and regulation of chromosome dynamics in early mitosis, using our newly developed assay.