Every time a human cell divides, its chromosomes must be physically reshaped—sister chromatids are pulled apart and each one is compacted—before they can be correctly separated into two daughter cells. These two structural changes, called sister chromatid resolution and chromosome compaction, are driven by two related protein complexes, condensin II and condensin I, but it is unknown how their timing is coordinated or whether a breakdown in that coordination leads to the chromosome missegregation seen in many cancers. This project will use live-cell imaging and advanced genomic techniques to watch the process unfold in real time, revealing how the two condensin complexes work in sequence and what happens when that sequence goes wrong. Because an abnormal number of chromosomes—a condition called aneuploidy—is a hallmark of advanced cancers and is linked to chemotherapy resistance and poor prognosis, understanding the fundamental mechanics of chromosome reorganisation could eventually point toward new ways to detect or treat chromosomal instability. This is primarily fundamental science: it asks how a core cellular machine works, not how to fix it yet, but past discoveries in chromosome biology have directly shaped cancer diagnostics and therapies.
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To ensure correct chromosome segregation in mitosis, chromosomes must undergo reorganisation in early mitosis (prophase and prometaphase). The mitotic chromosome reorganisation involves two major structural changes: First, sister chromatids are resolved from each other because of the removal of sister chromatid cohesion and DNA catenation (sister chromatid resolution). Second, each chromatid is compacted, making a wider and shorter chromosome (chromosome compaction). Mitotic chromosome reorganisation is promoted by the condensin complex, which contains two SMC proteins and three non-SMC proteins. In vertebrates, there are two types of condensin complexes, condensin I and II, which contain the same SMC proteins but different non-SMC proteins. While sister chromatid resolution is promoted by condensin II, chromosome compaction is driven by condensin I. Sister chromatid resolution happens 15-20 min earlier than chromosome compaction. However, it is still unknown how sister chromatid resolution and chromosome compaction are coordinated or whether such coordination is important for correct chromosome segregation. We will address how condensin I and II temporally coordinate sister chromatid resolution and chromosome compaction, how they balance the two processes, and how such coordination and balance ensure correct chromosome segregation. For our study, we will use a novel assay to analyse the kinetics of sister chromatid resolution and chromosome compaction in live-cell imaging. To complement this assay, we will also use Live FISH and Hi-C/micro-C. Meanwhile, an abnormal number of chromosomes (aneuploidy) is a hallmark of cancer cells. Aneuploidy occurs due to chromosome missegregation in mitosis. If cancer cells show frequent chromosome missegregation, such a state is called numerical chromosomal instability (N-CIN). Crucially, N-CIN is often found in the advanced stage of cancers and is frequently associated with chemotherapy resistance and poor prognosis. However, it is not fully understood how defects in mitotic chromosome reorganisation are linked to N-CIN in cancer cells. We will study how the impaired coordination or balance of sister chromatid resolution and chromosome compaction plays causative roles in the development of N-CIN in cancer cells. Through the study of physiology and pathology of mitotic chromosome reorganisation, our research will provide new insights into how chromosomes are prepared during early mitosis for correct segregation, and how defects in this process cause N-CIN and aneuploidy in cancer cells, thus affecting cancer development and prognosis.
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