Eukaryotic chromosomes undergo enormous changes in structure and organisation over the course of a cell cycle. One of the most fascinating changes is the transformation of interphase chromatin into rod-shaped mitotic chromosomes in preparation for cell division. This process, known as chromosome condensation, is a key step for the successful segregation of chromosomes during mitosis and meiosis.
The overall aim of our research is to unravel the action of molecular machines that organise the 3D architecture of eukaryotic genomes. Insights into the general working principles behind these machines will be of great importance to our understanding of how cells inherit a complete set of their chromosomes every time they divide and thereby prevent the emergence of aneuploidies, which are hallmarks of most cancer cells and the leading cause of spontaneous miscarriages in humans.
One of the central players in the formation of mitotic chromosomes is a highly conserved multi-subunit protein complex, known as condensin. We have shown that condensin encircles chromosomal DNA within a large ring structure formed by its structural maintenance of chromosomes (SMC) and kleisin subunits and then uses the energy of ATP hydrolysis to move along the DNA double helix. Our working hypothesis is that condensin uses this motor activity to extrude large loops of chromatin (figure 1) and thereby shapes DNA into mitotic chromosomes.
In an independent project, we use a newly developed time-resolved microscopy assay to follow the dynamics of chromosome condensation in live fission yeast cells (figure 2). The combination of in vivo and in vitro approaches enables us to gain a systems-level understanding of the mechanisms that shape eukaryotic genomes across scales.
We will continue to use a highly interdisciplinary approach to advance our understanding of the molecular machines that control genome architecture by combining approaches from biochemistry, molecular cell biology and structural biology. In collaboration with other research groups, we are expanding our technological repertoire to chemical biology and single-molecule biophysics to uncover the fundamental principles that control chromosome architecture.