Every time a cell divides, its long strands of DNA must be tightly packed into compact chromosomes—yet the role of the proteins that make up most of that package remains largely unknown. This project tackles a fundamental gap in cell biology. For 25 years, researchers have focused on non-histone proteins during chromosome condensation, even though histones account for 60% of a chromosome’s mass. The researcher’s recent discovery that DNA supercoiling reverses during mitosis in yeast suggests that nucleosomes—the spools of histone protein around which DNA wraps—change their arrangement or shape during cell division. This contradicts the long-held view that mitotic chromatin is a passive bystander. The work will first characterise chromatin states during mitosis in yeast and frog egg extracts, then build artificial chromosomes from scratch to test exactly how histones drive condensation. This is fundamental science with no immediate practical application. However, understanding how chromosomes assemble is essential for grasping what goes wrong when cells divide incorrectly—a hallmark of cancer and developmental disorders. Past fundamental discoveries about chromosome structure have underpinned everything from cancer diagnostics to gene therapy, and this project could similarly reshape our understanding of a process that happens trillions of times a day inside the human body.
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The compaction of chromosomes as cells enter mitosis is probably the most iconic process of dividing cells, yet is still poorly understood. Research over the last 25 years has focused on the function of the non-histone component of chromosomes, while the characterization of histones, which make 60% of the mass of chromosome, and chromatin states during mitotic chromosome formation has received little attention. Recently, my group demonstrated that minichromosomes in yeast cells undergo a rev ersal of DNA supercoiling during mitosis from minus to plus, as they are compacted by the condensin complex. Since canonical nucleosomes impose negative supercoiling, the implication of the finding is that the distribution and/or conformation of nucleosomes must be different during mitosis either transiently or stably. This realisation provides a radical departure from the view that mitotic chromatin is a passive factor during chromosome assembly and opens a new exciting question in the fiel d; what is the nature and functional role of the histone-component of mitotic chromosomes? The aim of this proposal is to uncover the mechanisms by which histones contribute to chromosome condensation. To understand chromosome condensation I will combine classical cell biology with cutting-edge genetic, molecular and biochemical techniques to comprehensively characterize the nature of chromatin during mitosis using S.cerevisiae and X.laevis as model systems. Following this characterization I will build chromosomes from scratch, so that I have full control over the components and activities involved in their formation, to question the mechanistic role of chromatin during chromosome condensation.
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