A Summary of the Science in our Lab
All functions of the genome depend on the dynamic three-dimensional architecture of chromosomes within the cell's nucleus. The aim of our research is to understand the fundamental mechanisms behind the machines that organize chromosomes.
A major aspect of our work is to uncover the molecular basis for the formation of mitotic chromosomes. This process, known as chromosome condensation, is a key step for the successful segregation of chromosomes during cell divisions. Insights into the general working principles will be of great importance to our understanding of how cells prevent the emergence of aneuploidies, which are hallmarks of most cancer cells and the leading cause of spontaneous miscarriages in humans.
A central player in the formation of mitotic chromosomes is a conserved multi-subunit protein complex known as condensin. We are using a combination of biochemistry, cell biology and structural biology approaches to study condensin function in yeast and mammalian cells. Read more...
Our knowledge of the inventory of proteins that drive chromosome condensation is still incomplete. To identify yet undiscovered condensation factors, we are using a microscopy-based quantitative chromosome condensation assay in live fission yeast cells. Read more...
Condensin complexes are built from a pair of Structural Maintenance of Chromosomes proteins (SMC2 and SMC4), a kleisin subunit, and two proteins that are composed of alpha-helical HEAT repeat motifs. The SMC subunits heterodimerize via a globular 'hinge' domain at one end of a long coiled coil. The kleisin subunit connects the two SMC ATPase 'head' domains at the other end of the coils to create a large ring-shaped structure.
We have discovered that condensin encircles chromosomal DNA within the ring. Our working hypothesis is that condensin uses this topological principle to link chromatin fibers.
We now want to understand how condensin rings are loaded onto DNA to generate chromosome linkages.
Our chromosome condensation assay measures the distance between two fluorescently marked chromosome regions simultaneously in large numbers of fission yeast cells as they go through mitosis. We then apply automated image analysis routines to extract quantitative condensation parameters from the time-lapse recordings. We have used this method to screen through a large number of mutants with the aim of identifying novel regulators of chromosome condensation. We are currently investigating the first candidate genes identified in our screen.
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