Häring Group

Previous and current research

Eukaryotic chromosomes undergo enormous changes in structure and organisation over the course of a cell cycle. The most fascinating of these changes was first observed by cell biologists more than 125 years ago; as cells prepare for cell division, sister chromatid pairs individualise into highly condensed rod-shaped structures, which attach to the mitotic spindle via their kinetochores. Once all sister kinetochore pairs have attached in a bipolar fashion, the connection between sister chromatids is released to trigger their segregation towards opposite cell poles. These ordered events ensure that every daughter cell inherits a complete set of chromosomes. Errors during chromosome segregation lead to aneuploidy, a hallmark ofmost cancer cells and the leading cause for spontaneous miscarriages in humans.

The overall aim of our research is to understand the action of molecular machines that organise chromosomes prior to and during cell divisions. Recent research has identified two highly conserved multi-subunit protein complexes called cohesin and condensin as central players for chromosome segregation. Both complexes are composed of heterodimers of SMC (structural maintenance of chromosomes) subunits whose ABC ATPase head domains are connected by so-called kleisin subunits to form gigantic tripartite ring structures.

A body of evidence supports the notion that the cohesin complex holds sister chromatids together by entrapping them within its ring structure (figure 1) until a protease named separase opens the ring by site-specific cleavage of cohesion’s kleisin subunit and thereby initiates chromosome segregation. Our working hypothesis is that condensin uses a similar topological principle to stabilise loops of chromatin in order to give mitotic chromosomes their characteristic shape (figure 2).We use an interdisciplinary combination of biochemistry, molecular biology, cell biology and, in collaboration, chemical and structural biology to discover how these two protein complexes function at the molecular level in yeast and mammalian cells.

In an independent project, we are exploring novel approaches to identify additional players that direct the formation of mitotic and meiotic chromosomes using genetics and time-resolved light microscopy methods.

Future projects and goals

Our major goal is to elucidate the fundamental molecular mechanics behind the organisation of mitotic chromosomes on different levels. We will initially focus on the following three questions:

• How does the condensin complex bind to chromosomes, how does it function on chromosomes, and how is its activity controlled?
• How does the interplay of condensin with DNA and other chromosomal proteins ultimately shape a mitotic or meiotic chromosome?
• What other key components are required for making a mitotic chromosome?