Chromosome segregation during human cell division

"[A]ll life on Earth shares the same basic DNA structure." This statement by Francis Crick, who won the Nobel Prize for co-discovering the structure of DNA, highlights the fundamental role genes play in our lives. The genes we pass on to our children determine their identity just as our own genes ensure that we remain individuals with an unmistakable appearance and traits throughout our lives. These apparently self-evident fundamental characteristics of life are rooted in the fact that our genome, that is, the entirety of our hereditary information, is passed on to daughter cells each time a cell divides. In this way, every cell in the body receives a near-identical copy of our genome, and when an ovum is fertilized by a sperm cell, a new genome - a set of "blueprints" for a new individual - is created. For a long time now, we have known that those blueprints are stored in the form of DNA on a total of 46 chromosomes. In the cell division process, these chromosomes are copied by way of DNA replication and then passed on to the daughter cells as they form. But how does this process ensure that each daughter cell contains a full set of chromosomes and not an incorrect number or combination of them? Such a state can often be observed in tumour cells, and if a chromosome is distributed incorrectly in the formation of human ova, it may lead to conditions such as Down Syndrome. Jan-Michael Peters` work has made a major contribution to answering this significant question in biomedicine. Peters and his team have shed light on the regulation and functioning of various protein molecules which are essential for the correct segregation of chromosomes in human cell division. Like the components of tiny devices, most of these proteins act as parts of "molecular machines." One of these machines, the cohesin complex, links the two DNA molecules (also known as sister chromatids) found in each chromosome after replication. The resulting bond between sister chromatids then plays a key role in ensuring the correct segregation of chromosomes. The process of chromosome segregation itself is also controlled by complicated molecular machines - and Peters and his team have discovered how they work, too. These protein complexes, known to experts as APC and separase, perform the important task of removing cohesin complexes from chromosomes. In order to ensure the correct distribution of chromosomes, however, this step cannot be initiated until all 46 chromosomes have been connected to the two poles of the dividing parent cell. If the cohesin complexes are removed from chromosomes too early, the sister chromatids may be distributed incorrectly, which can have catastrophic results for the daughter cells (and for the person in question). Therefore, Jan-Michael Peters` work has not only enriched our knowledge of the mechanisms involved in genome inheritance, but also helped us understand the origins of conditions arising from incorrect chromosome distribution.

Genomes are large compared to the cells they are contained in, corresponding to two meters of DNA which are contained in the 46 chromosomes of human cells. At the various stages of the lifetime of a cell, different genes contained in this large genome have to become active. The genome also has to be duplicated and passed on to daughter cells during cell division, and defects in the genome have to be repaired. For these processes it is crucial that the genome is folded correctly. During this Wittgenstein project, we discovered that a key molecule mediating this genome organization is cohesin, a large ring--shaped protein complex initially discovered for its essential role in chromosome segregation. Our work indicates that in addition to contributing to chromosome segregation in dividing cells, cohesin has a universal role in all cells in forming DNA loops. Several observations imply that cohesin forms these by a mysterious DNA pumping mechanism. This loop extrusion mechanism enables cohesin to connect distant genomic regions which are specified by a DNA binding protein, called CTCF. The size and lifetime of these loops are controlled by yet another protein, WAPL that can release cohesin from DNA and thereby destroy loops. Our work indicates that the ability of cohesin, CTCF and WAPL to form and dissolve DNA loops determines how the genome is folded in chromosomes and that these processes contribute to gene regulation. We further suspect that defects in this process contribute to the development of tumor cells. This hypothesis could explain why cohesin subunits are among the most frequently mutated genes in human cancers.