20 February

Thesis defense Timo Kuijt: Regulation of spindle assembly checkpoint signaling and silencing during mitosis

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Timo Kuijt, from the group of Geert Kops, successfully defended his thesis “Regulation of spindle assembly checkpoint signaling and silencing during mitosis” the 20th of February. During his PhD, Kuijt studied the functioning of the spindle assembly checkpoint, which is involved in the correct distribution of chromosomes during cell division. If this is not done properly, this results in cells with too many or too few chromosomes, one of the hallmarks of cancer cells.

Distribution of chromosomes
The development, growth and maintenance of a healthy body depend on the structural replenishment and renewal of cells, the miniscule units that make up our body. Through cell division, or mitosis, one mother cell splits into two identical daughter cells. For this, all chromosomes in the cell are first copied and then those copies must be distributed fairly among the daughter cells. For example, errors in the division, or segregation, of the copies can cause one daughter cell to have too many chromosomes and the other too few. A cell with too many or too few chromosomes is called aneuploid, and this can cause the cell to become unstable. Aneuploidy is one of the hallmarks of cancer.

Cell division and the segregation of the chromosome copies. Credit and copyright: Timo Kuijt.

Network of pull wires
To ensure that the chromosome copies are correctly distributed between the two daughter cells, each copy must be pulled to one side of the cell by the mitotic spindle. The mitotic spindle is an organized network of pull wires (microtubules) that pull the chromosome copies to two opposite sides of the cell. Before the spindle can pull the copies apart, one copy must be connected to microtubules from one pole of the cell, while the other copy must be connected to microtubules from the other pole. Only when all chromosomes are connected to the microtubules in this way a signal is sent to the spindle that the chromosome copies may be pulled away from each other.

Spindle assembly checkpoint
One of the mechanisms that ensures that the chromosome copies are not pulled away from each other too early is the spindle assembly checkpoint. This mechanism is a signal that is active on the chromosome copies that are not yet connected to microtubules. The segregation of the chromosomes is inhibited by this signal. The enzyme MPS1 regulates the spindle assembly checkpoint: this enzyme binds to chromosome copies that are not connected to microtubules, ensures that other components of the spindle assembly checkpoint can also bind, thereby inhibiting cell division. During his PhD, Kuijt studied the workings of the spindle assembly checkpoint and how the activity of the MPS1 enzyme itself is regulated.

For a long time, it was not known whether the mere binding of microtubules to the chromosome copy is enough to turn off the signal from the spindle assembly checkpoint, or whether these microtubules are also required pull on the chromosome copy. Kuijt discovered that the binding of microtubules is sufficient, without the tensile force from these microtubules, to turn off the signal.

The mitotic spindle (yellow wires and dark pink poles) and chromosomes (light pink) just before the segregation of the chromosomes. Credit en copyright: Timo Kuijt.

Sensor
In addition, Kuijt developed a sensor that can measure the activity of MPS1 distinct locations in the cell. He then disabled several genes that may be involved in the activation of MPS1, and therefore in the activation of the spindle assembly checkpoint. He discovered that a number of these genes regulate the activation of MPS1, and therefore also the activity of the spindle assembly checkpoint.

Lastly, Kuijt showed with this new sensor that MPS1 is less active in colon cancer cell lines. This may cause a less strict spindle assembly checkpoint, and therefore a higher chance of incorrect distribution of the chromosomes during cell division. The sensor can be used to study the influence of MPS1 on the correct distribution of chromosomes in healthy and diseased models in the future, as Kuijt uses this new sensor in mini-organs grown from healthy colon cancer cells and cells from a colon cancer tumor.

 

 

 

Timo Kuijt did his PhD research in the group of Geert Kops.

Copyright of the images on this page belongs to Timo Kuijt.