Every time a human cell divides, it must squeeze two metres of DNA into compact, rod-shaped chromosomes that can be pulled apart without tangling or breaking—and this project aims to understand exactly how that happens. Errors in this process are devastating. When chromosomes fail to separate properly during egg or sperm formation, the result can be Down syndrome or miscarriage. In dividing body cells, the wrong number of chromosomes—a condition called aneuploidy—is a hallmark of many cancers. Yet the molecular machinery that builds and moves chromosomes remains incompletely understood. The researcher will tackle three linked questions. First, how do chromosomes condense into their compact mitotic shape, and what roles do histone modifications and the condensin complex play? Second, how do centromeres—the attachment points for the machinery that pulls chromosomes apart—get their identity and assemble the kinetochore? Third, how does the chromosomal passenger complex coordinate the timing and accuracy of segregation? This is fundamental science. There is no immediate clinical application. But understanding the basic mechanics of chromosome segregation has historically been essential for diagnosing genetic disorders, developing cancer therapies, and improving fertility treatments. A deeper grasp of these processes could eventually reveal new targets for drugs that block cancer cell division or prevent chromosome errors in reproductive medicine.
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My research career has been driven by a desire to understand how the genome is packaged into compact chromosomes that segregate accurately to daughter cells during cell division. Properly regulated chromosome structure and segregation are critical for human health - errors during meiosis cause Down syndrome and spontaneous abortions. Furthermore, somatic alteration of chromosome number, or aneuploidy, can contribute to the pathogenesis of cancer. During the next five years I aim to answer the following questions: Making the mitotic chromosome: How do mitotic chromosomes condense, and what is the role of histones and non-histone proteins in shaping them? We will explore the role of histone modifications and the condensin complex in mitotic chromosome condensation and structural integrity. We will understand the structure/function of the chromosome periphery through crosslinking/mass-spectrometry, development of a novel in vitro biotinID method for mapping protein neighbourhoods th roughout chromosomes and elsewhere in cells, and gene targeting/manipulation studies focussed on the chromosome periphery scaffolding protein Ki-67. Segregating the chromosomes: How are centromere specification and kinetochore assembly controlled epigenetically? Using novel synthetic human chromosomes, we will probe interactions between centromeric chromatin and pericentromeric heterochromatin. We will develop a new synthetic modular PREditOR (Protein Reading and Editing of Residues) approach to manipulate and functionally characterise protein modifications in chromatin and more generally. Controlling the process: How does the chromosomal passenger complex (CPC) regulate chromosome segregation? We will study CPC interactions with other kinases and determine how RalA and its GEF TD-60 modulate CPC activity in mitosis.
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