24 September

Thesis defense Spiros Pachis: Advance to GO

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Spiros Pachis from the Kops group successfully defended his thesis “Advance to GO: Regulation of mitotic progression by the spindle checkpoint kinase MPS1” on the 24thof September. During his PhD, Pachis studied the involvement of the protein MPS1 in ensuring the correct segregation of chromosomes during cell division.

Cell division
Cell division or mitosis is a crucial biological process that ensures the propagation of cellular properties in future generations of cells in all organisms. In humans it is important for development and growth, as well as the replenishment of cells that die naturally or are injured every day.

Chromosome segregation
Most heritable information is encoded in the DNA, the genetic material of the cell. Chromosomes are the structural units of DNA and human cells contain 46 of them, 23 inherited from the mother and 23 from the father. For cells to remain healthy and be able to execute all of their biological processes, it is essential that all of the chromosomes are copied and then distributed equally between the two daughter cells that arise after each cell division. Genetic imbalances brought about by the faulty segregation of chromosomes is responsible for a multitude of developmental syndromes and diseases. Aneuploidy, the situation in which a cell contains either more or fewer chromosomes, is one of the hallmarks of cancer.

Checkpoints
Due to its extreme importance, chromosome segregation is a highly regulated and complex process that is driven by the mitotic spindle. The spindle is comprised of microtubules which function as a sort of fishing rod that can grow and shrink. Microtubules contact the chromosomes which have been previously duplicated, capture them and reel them in towards the spindle pole they originate from. The goal of mitosis is for the microtubules of one pole to capture and reel in a copy of every chromosome while microtubules originating from the opposite pole need to capture the other copy. This ensures that at the end of mitosis each daughter cell inherits an exact copy of all the chromosomes from the parent cell. There are two cellular systems in place to monitor and ensure the equal segregation of chromosomes: the spindle assembly checkpoint and the error correction pathway.

Chromosome segregation. After duplication of the chromosomes, microtubules start to attach and the chromosomes line up in the middle of the cell. Once all the chromosomes are connected to microtubules, the duplicated copies are pulled towards opposite poles of the spindle. | Chromosoomsegregatie. Na het kopiëren van de chromosomen hechten de microtubili zich aan de chromosomen en gaan de chromosomen op een rijtje liggen in het midden van de cel. Wanneer alle chromosomen verbonden zijn met microtubili worden de gekopieerde chromosomen naar de tegenoverliggende kanten van de cel getrokken.

Master regulator
During his PhD, Pachis studied the role of an important protein, MPS1, in the correct segregation of chromosomes during cell division. MPS1 essentially monitors whether chromosomes are captured by microtubules and prevents them from being reeled in unless all of them have formed stable attachments to the spindle. He found that MPS1 binds to the chromosomes in the same region that the microtubules do. When microtubules are not connected to chromosomes, MPS1 binds to the chromosomes and prevents them from being segregated. As soon as microtubules capture a chromosome, MPS1 is kicked off and can no longer perform its function, allowing segregation to happen when all chromosomes are captured. Pachis further found that different parts of the MPS1 protein interact with each other and that this is important for MPS1 to bind to the chromosomes at the right place and the right time, but also to let go once microtubules are attached. Finally, Pachis found that different levels of MPS1 are needed on the chromosomes for the different functions of the protein in the spindle assembly checkpoint and the error correction pathway. This may explain what happens during cell division, when MPS1 levels on the chromosomes are gradually reduced as more and more microtubules become attached.

When microtubules are absent, chromosomes (blue) are not organized and MPS1 is bound (green dots). When microtubules (red rods) are bound to the chromosomes, the chromosomes line up in the middle of the cell and MPS1 can no longer be seen. | Wanneer microtubili niet aanwezig zijn zijn de chromosomen (blauw) niet georganiseerd en is MPS1 (groene stippen) gebonden aan de chromsomen. Wanneer de microtubili (rode lijnen) gebonden zijn aan de chromosomen, gaan de chromosomen op een rij liggen in het midden van de cel en is MPS1 niet langer aanwezig.

 

Spiros Pachis first came in contact with the work done in the group of Geert Kops after following an inspiring course about Cell Division and Chromosome segregation taught by Kops. This led to Pachis writing his master thesis under his supervision and eventually in Pachis asking for, and being offered, a position as a PhD student in the Kops group, the results of which comprise his thesis.

 

 

Geert Kops is group leader at the Hubrecht Institute, professor of Molecular Tumor Cell Biology at the University Medical Center Utrecht, Oncode Investigator and Scientific Director of Oncode Institute.