Discovery of protection against cell division failures
In the current issue of “Cell”, ETH researchers describe the causes for division errors of human tissue cells and how the cells protect themselves against these.
The human body is made up of billions of cells which constantly divide, even in adults. This is how tissues are renewed and any damages repaired. Normal cell division follows a fixed pattern: the chromosomes in a cell are duplicated and then redistributed so that two identical chromosome clusters are generated. A cleavage furrow then ingresses between the two chromosome clusters, which then form distinct cell nuclei. The cleavage furrow deepens and finally completely separates the original cell into two daughter cells. Both contain their own cell nucleus.
However, Daniel Gerlich, professor at the Institute for Biochemistry at ETH Zürich, and his group are interested in the cases when something goes wrong in the cell division process. Sometimes the cell begins to divide, forms two cell nuclei, but cannot complete the division process. In these cases, the cleavage furrow regresses and the cell does not divide. This creates a cell with two nuclei. These cells are called tetraploid cells and are thought to be precursors of cancer cells.
Chromosome bridges impede cell division
Gerlich’s group investigated the causes leading tetraploidization. Using special labelling techniques, they were able to observe the details of what went wrong in the division of living cells under an optical microscope. “We saw that in some dividing cells a connection containing chromosome material remained between the two nuclei”, Gerlich reports. These faults in cell division are called chromosome bridges. Until now, their effect on the cells was not clear. The group was able to show that chromosome bridges often caused tetraploidization. The undivided chromosome parts appear to impede the final separation of the two daughter cells.
However, not every chromosome bridge led to a tetraploid cell. Observation over long periods of time showed that many of the partially divided cells with chromosome bridges later completed cell division. On closer investigation, however, the researchers discovered that the process was slower compared to cells without chromosome bridges. “We concluded that there must be a mechanism which helps the cell to divide successfully, even if it takes slightly longer”, Gerlich explains.
Aurora B delays cell division until chromosome bridges resolve
The researchers identified the already known enzyme Aurora B as an important player in the process. “We noticed that Aurora B stayed active for longer in cells with chromosome bridges”, Gerlich reveals. When Aurora B was active, the daughter cells did not fully separate. The cellular canal containing the chromosome bridge remained open at first, giving the chromosomes enough time to separate. As soon as this was completed, Aurora B was inactivated. This was then the signal for the two daughter cells to fully separate.
When the researchers artificially switched off Aurora B in the experiment, cell division failed as the chromosome bridges formed a barrier. As a result, the cleavage furrow regressed. The daughter cells were not separated and the cell nuclei remained together in the original cell, thus making it tetraploid.
“The experiments suggest that Aurora B responds to non-separated chromosomes and is part of a protective mechanism that ensures that the final step of cell division is only initiated when all chromosomes have been fully separated”, Gerlich explains. Aurora B therefore helps most cells to divide perfectly, even if they have initial difficulties.
Breakthrough thanks to new methods
In order for the researchers to observe the cell division process in detail, they first had to make it visible. They developed their own labelling methods and adapted existing ones. “The use of fluorescent protein markers was key to identify fine structures such as chromosome bridges under an optical microscope, and to follow their development”, Gerlich states.
used automated microscopic video recordings to observe the division of
thousands of cells for up to 100 hours. As such data require specialized tools
for appropriate analysis, part of the research group works on the development
of new computational image processing methods. In order to handle the huge
amounts of data generated, the group will soon have to upgrade their storage
capacity well into the realm of terabytes.
Steigemann P, Wurzenberger C, Schmitz MH, Held M, Guizetti J, Maar S, Gerlich DW. Aurora B-mediated abscission checkpoint protects against tetraploidization. Cell. 2009 Feb 6. 136(3). 473-84.