Chromosome attachment and aneuploidy – chromocatch
Together against cancer: CATCH YOUR CHROMOSOMES!
In cancer cells, a defect during cell division leads to the appearance of an aberrant number of chromosomes, probably du to defective chromosome capture and/or attachment. It is therefore essential to unravel the precise mechanisms leading to correct chromosome capture, attachment and segregation in cells.
Mechanisms of chromosome capture and segregation
Do you know that while you are reading this paragraph, more than 20 millions of cells in your body are dividing? Do you know that during each cell division, these cells have to faithfully segregate 23 chromosomes? Any mistake during this process can be really serious. Indeed, an increased frequency of chromosome loss is observed in cancer cells and this phenomenon is proportional to tumour aggressiveness. Thankfully, cells have developed sophisticated mechanisms to prevent the appearance of chromosome attachment defects. Our laboratory is studying these cell cycle mechanisms in order to better understand how cells can fairly separate chromosomes into each daughter. Recent advances in cell biology identified the key players required to coordinate cell division with chromosome separation. These players are ideal targets to develop new drugs against cancer. The success of drugs such as taxol, which targets microtubules, encourages the development of new compounds against components of the chromosome segregation machinery. Our research project funded by the ANR will lead to fundamental and general knowledge of the mechanisms required to separate chromosomes.
The use of model systems such as yeast is clearly an advantage because the mechanisms involved in the division of this organism is conserved, although less complex than human cell. This system model was, for example, used by Dr Paul Nurse, Tim Hunt and Lee Hartwell to discover fundamental and conserved mechanisms of the cell cycle (Nobel prize of medicine 2001). During the last decade, new tools in genetics and microscopy were set up to investigate major mechanisms in cell biology. For example, it is now possible to follow cell division in live cells with multiple molecular markers. Recently, we developed optical tools including laser microsurgery in order to investigate biological forces in live cells. Using these tools we can now quantify the consequences of specific gene mutations on the quality of chromosome separation.
We have generated a mathematical model, which reproduces chromosome separation in cells. This small «chromosome segregation machine« is entirely generated from live cell videomicroscopy analysis. Interestingly, this model can faithfully separate virtual chromosomes with accuracy comparable to cells. Using these new tools, we determined the fundamental mechanisms required to separate chromosome with time and accuracy. For example, each daughter cell inherits a perfect set of chromosomes after cell division. We can now use our model to predict what are the key players in chromosome separation using a combination of molecular genetics and mathematical modeling.
Our chromosome separation model highlight how interdisciplinary approaches will help us in the near future to understand how cells divide. It is clear that cell division is much more complex than just chromosome separation. For example, we have no idea how chromosome arms are segregated. In the next couple of years, new players will be integrated in our model in order to take in account the biological cell reality. This new way of thinking will open some new biological field of investigation to fully understand cell division.
We have recently published our mathematical model in a renowned Cell Biology journal:
Gay et al. (2012); A stochastic model of kinetochore–microtubule attachment accurately describes chromosome segregation. J Cell Biol. Mar 19;196(6):757-74.
A highlight about this work has also been published in the same issue:
Ben Short, Simulating segregation , J Cell Biol 2012 196:666.
The accurate segregation of sister chromatids to daughter cells requires both the bipolar attachment of centromeres to the mitotic spindle and a correct coordination between chromosome segregation and cytokinesis. The cell division axis is defined by the position of the centrosomes, which generate the mitotic spindle. Cytokinesis always takes place perpendicularly to this axis, once chromosomes are segregated. These different events are coordinated in order to prevent the formation of aneuploid cells, a phenotype frequently observed in cancer and genetic diseases. The precise mechanisms leading to aneuploidy is unknown but is likely to be caused by either a defect in chromosome segregation or a defect in the coordination between segregation and cytokinesis. By a combination of genetic, video-microscopy and mathematical modeling, the aim of this project is to characterise the mechanisms leading to aneuploidy.
Project coordination
Sylvie TOURNIER (UNIVERSITE TOULOUSE III [PAUL SABATIER]) – tournier@cict.fr
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Partner
UPS Toulouse 3 - LBCMCP UNIVERSITE TOULOUSE III [PAUL SABATIER]
Help of the ANR 417,491 euros
Beginning and duration of the scientific project:
- 48 Months
