Mechanisms of spindle checkpoint silencing

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This project is about understanding how cells ensure chromosomes are segregated equally to daughter cells. Human beings are built from around 100 trillion individual cells. Each cell contains 46 chromosomes into which is packaged our genetic material (DNA, deoxyribonucleic acid), which provides the instructions for how a cell should work and how a whole organism should be built. This huge number of cells originates from a single cell that is the result of fertilization of an egg with a sperm. This single cell needs to be able to divide itself to generate two new daughter cells, which then also divide to produce further cells; this process repeats until the correct number of cells are generated. Moreover, cells do not live forever and are constantly being replaced by new ones. Thus, cell division is fundamental to the existence of life. A key part of cell division involves the accurate separation of the chromosomes into the two daughter cells - a process called mitosis. It is crucial that each daughter cell receives a complete set of chromosomes. We know that having the wrong number of chromosomes is a cause of multiple human diseases, most notably cancer where greater than 80% of human tumors have the wrong number of chromosomes. Indeed, altering chromosome number experimentally in mice has been shown to cause cancer. Secondly, many developmental disorders are the result of mistakes in chromosome separation such as Downs Syndrome, in which cells have an extra copy of chromosome 21. A large proportion of miscarriages are also caused by problems in chromosome separation. It is clearly vital that we work out how the process of chromosome segregation is controlled and why these controls are defective or over-ridden in these diseases. Each chromosome is made up of two sister chromatids that are stuck together after the cell replicates its DNA. To separate these two sister chromatids (one to each of the two daughter cells), the cell makes use of molecular cables called microtubules. Each sister chromatid has a "hook" called the kinetochore, which can attach to the end of a microtubule cable. As the cables attached to the two sister chromatids grow and shrink the chromosomes are moved around inside the cell. This jostling motion allows the chromosomes to line up in the middle of the cell. When everything is ready, the glue joining the two sister chromatids is removed and the sister chromatids are pulled to opposite daughter cells.But how is this process controlled? It turns out that the kinetochore also operates as the control centre for a monitoring system, called the spindle assembly checkpoint, which ensures that sister chromatids do not separate until the alignment process is complete. We have recently discovered the central players in this process but we do not yet understand how they are controlled nor how this system operates.The experiments that we will do will help answer these exciting and intriguing questions and therefore advance our understanding of how chromosomes are separated equally into daughter cells during cell division. To do this we will use state-of-the-art imaging technology (powerful microscopes) and modern techniques in molecular genetics and biochemistry to observe how chromosomes move in living cells and how the factors involved operate. The answers to these questions will help the identification of new targets and therapies to combat disease.