Cell division is one of life’s most fundamental processes. For example an adult human consists of about 100 trillion cells, all formed by division from a single fertilised egg cell. It is such a large number that if all our body’s cells were laid side by side, the chain of cells would circle the Earth about 100 times. However, the ability of cells to divide plays a decisive part not only in the development of an organism but also afterwards. This is because most cells need continual renewal. In an adult human, for example, 50 million cells die every second, while almost an equal number of new ones are formed in the same period of time. The decisive factor in all this is that each single one of the new cells contains the same genetic information as the original cell. To guarantee this, the duplication and dividing up of the genetic information are subject to the most stringent checking mechanisms. If the division is incorrect, either the resulting cells die or, even worse, develop into cancer cells.

The precision with which cells are able to divide without errors also fascinates ETH Zurich Professor Matthias Peter(1). For several years his group at the Institute for Biochemistry has been working on the control mechanisms which guarantee that cell division proceeds smoothly. They succeeded only recently in identifying an important factor in this process, the protein Cullin3 (Cul3). They published their work in the scientific journal Developmental Cell in the week beginning 4 June 2007 (2).

From worm to human

Cul3 was already known from the nematode worm called Caenorhabditis elegans, where the protein is an important component of the waste disposal machinery (3)(4). In this process, Cul3 labels proteins that need to be disposed of by attaching one or more ubiquitins to them. However, cells lacking Cul3 showed a wide variety of defects. In the case of Cul3 mutant cells, for example, cell division was severely disturbed, and often the cells were unable to separate from one another after division of the genetic material. This caused the formation of cells with several cell nuclei, which accordingly also contained multiple copies of the genetic material. Altogether, these defects cause the nematode to die prematurely, which makes the study more difficult. Izabela Sumara, a post-doctoral student in Peter’s laboratory, says “The aim now was to find out whether Cul3 also influences cell division in humans, and if it does, what its role appears to be.”

The researchers did indeed discover that the absence of Cul3 in human cells also causes cells with multiple nuclei (Figure 1). However, closer examination of this incomplete division revealed that not only did the cells contain multiple nuclei but also the number of chromosomes per cell nucleus was incorrect. The general rule is that during every cell division the chromosomes, which have already been duplicated, congregate in the centre of the cell, from where they are each pulled into one extremity of the cell by thin thread-like structural proteins called microtubules. A check is made during this process to ensure that each daughter cell contains the same type and number of chromosomes. Part of this check is that the microtubules do not start to pull until all the chromosomes are lined up in the centre of the cell.

The ETH Zurich researchers were now able to show that in the absence of Cul3, the microtubules begin to pull too soon, causing the chromosomes to be distributed non-uniformly (Figure 2). If Cul3 is missing, the genetic material can no longer be passed on to the daughter cells in a reliable way.

Fig. 1: If Cul3 is absent (left photo), cells with several nuclei (blue) are often formed during cell division. The microtubules (green) illustrate the dimensions of the cells. (Photos: Izabela Sumara) large

This endangers the regularity of the chromosomes and the stability of the genome. Peter explains that “It is important that we understand how this stability can be preserved, since although faulty chromosome distribution need not necessarily develop into cancer, nevertheless all cancer cells show defects of this kind.”

The end of a dogma?

However, Cul3 does not exert its influence on cell division on its own. The team of researchers discovered that Cul3 binds directly onto the chromosome passenger protein Aurora B. Together with three partners, Aurora B sits on the chromosomes in the initial phase of cell division and is responsible for their correct separation. In addition it is also needed to complete the physical division of the cells. The ETH Zurich Professor’s group showed that Cul3 labels Aurora B by attaching several ubiquitin proteins to it, thus affecting its functioning. As mentioned above, this kind of labelling normally means the destruction of the labelled protein. However, that is still not clear in the case of Aurora B, since there is no indication that Aurora B is degraded at an early stage. Peter explains that “We could also imagine that Aurora B is not destroyed after labelling, but that this is simply a signal for it to detach from the chromosomes.” However, if Aurora B is only labelled by this multiple ubiquitining and is not degraded, this would contradict an old dogma according to which all proteins to which several molecules of ubiquitin are attached are approved for destruction.

However, since up to now it was not possible to prove or disprove either of the two alternatives, one of the researchers’ most important aims is to find out which is correct. Izabela Sumara thinks this question might be answered by using an artificial Aurora B that can no longer be ubiquitined. The researchers are also extremely interested in finding out whether Cul3 has any other binding partners in addition to Aurora B. Matthias Peter hopes that “If we succeed in solving the function of additional binding partners for Cul3, we will have come another step closer to understanding the fascinating process of cell division.”

Fig. 2: If Cul3 is disabled, the chromosomes (green and central column, kinetochore stained) are pulled into the cell extremities by the microtubules (red and right-hand column) prematurely during cell division. This causes instability of the genome. large