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Splitting up is hard to do


26 Oct 2000

Scientists at the IMP have identified a universal mechanism which regulates the distribution of genetic information in dividing cells.

For the past 25 years, Kim Nasmyth has devoted his professional life to yeast. He is neither baker nor brewer but a highly esteemed geneticist, and he is obsessed with the idea of unravelling one of the most fundamental processes in living beings: cell division. To give his audience an idea of what it's all about, he likes to entertain them with a little riddle:

Two blind men are on a shopping-binge. Each of them buys a pair of blue socks, a pair of grey socks and a pair of black socks. Upon leaving the shop they realize that all six pairs have ended up in one bag. How can they make sure - without any help by a seeing person - that they will take home what they actually wanted: three different coloured pairs of socks?

The answer is to pull the pairs apart and cut the tiny threads that attach the matching socks to each other. Each person then takes one half of each pair. This simple and elegant solution illustrates, in the eyes of the biologist, the underlying principle of cell division (mitosis). Think of the socks as chromosomes, of which every human cell (except egg- and sperm-cells) has 23 pairs. Every time a cell divides it has to make sure that both daughter-cells will end up with exactly the same number of chromosomes. 

Because this is such a delicate and important process, there are sophisticated control-mechanisms within the cell. If, despite these controls, cell division goes awry, the resulting daughter cells can contain either too many or too few chromosomes (aneuploidy). Such molecular accidents can have severe consequences for the organism in which they occur. Aneuploidic cells, for example, can be found in most solid malignant tumours. If chromosomal aberrations occur during meiosis (a somewhat different kind of cell division that leads to egg- and sperm-cells), they can cause severe birth defects such as Down-syndrome (trisomy 21). Not surprisingly, biologists and doctors are very keen to understand the exact mechanism of chromosomal segregation in mitosis and meiosis.

The first person to actually witness a cell division through a microscope was the German zoologist Otto Btitschli back in 1875. The basic steps in the process were soon identified: before a cell divides, its chromosomes duplicate but remain attached to each other. In an event known as metaphase, the chromosomes align along the cell's equator. The two halves, the so-called sister chromatids, appear to be tightly glued to each other, while at the same time being pulled in opposite directions by the mitotic spindle. The two counteracting forces seem to compensate each other, until - very suddenly - the connections between chromosome halves give way. During the subsequent anaphase the sister chromatids are rapidly pulled apart and cell division is completed. Both resulting daughter cells end up with a complete set of chromosomes. 

For the past 125 years, however, scientists have been puzzled by two main questions: what is the nature of the "molecular glue" that keeps sister-chromatids together and how is this tight cohesion finally snipped apart? Looking back at our riddle, we would want to identify the tiny threads connecting socks and the scissors that cut them apart.

Scientists at the Research Institute of Molecular Pathology (IMP) in Vienna, Austria, can now provide the answers to those questions. A group of yeast geneticists headed by Kim Namsmyth, has been able to identify a protein complex responsible for sister chromatid cohesion. The complex was given the name cohesin. Subsequently, Frank Uhlmann in Nasmyth's team discovered the enzyme which cuts cohesin and works just like a pair of molecular scissors. He called it separin or separase. For separin to become active it has to be released from the grips of another protein named securin.

The details of Uhlmann's findings will be published in the coming issue of the American science journal CELL (October 27th, 2000). Two additional articles by other IMP scientists will accompany the paper. Their contents not only compliment Uhlmann's discovery but rather add a new dimension to them, suggesting that a universal principle among living beings has been identified. The Italian PhD student Sara Buonomo, also in Nasmyth's team, was able to show that the same mechanisms that regulate chromosome segregation in mitosis are also at work in meiosis in yeast.

The latest and most surprising news came from IMP group leader Jan-Michael Peters and his co-workers Irene Waizenegger and Silke Hauf. They have been able to confirm that the mechanisms that work in yeast are basically identical in humans. This is quite a sensation since earlier studies have invariably yielded negative results. Although a cohesin-like protein has been known to exist in humans, it seemed to disappear from chromosomes long before metaphase was reached. The IMP scientists now discovered that small amounts of cohesin remain on human chromosomes and are cleaved at the onset of anaphase. The enzyme responsible for cleaving is very similar to yeast separin. From these discoveries the scientists conclude that they have indeed found a universal principle which regulates the equal distribution of genetic material in cell division in presumably all eukaryotic organisms from yeast to man. By describing these mechanisms they have elucidated one of the oldest mysteries of biology. Their contributions will provide a better understanding of chromosomal missegregation and related diseases such as cancer.

Original Publications:

Ullmann et al.: Cleavage of Cohesin by the CD Clan Protease Separin Triggers Anaphase in Yeast. Cell 103:3, 375-386, 27 October 2000.

Waizenegger et al.: Two Distinct Pathways Remove Mammalian Cohesin from Chromosome Arms in Prophase and from Centromeres in Anaphase. Cell 103:3, 399-410, 27 October 2000.

Buonomo et al.: Disjunction of Homologous Chromosomes in Meiosis I Depends on Proteolytic Cleavage of the Meiotic Cohesin Rec8 by Separin. Cell 103:3, 387-398, 27 October 2000.