Elucidating the role of the nuclear envelope in centriole duplication

点击翻译按钮获取中文摘要

Our bodies are made from billions of cells, but we start from just a single fertilised egg that divides into two, then four, then eight cells etc. Once these cells become a functioning organism, many cells continue to divide and help re-generate damaged tissue. Sometimes cell division goes wrong and cells are made that divide uncontrollably, producing cancerous tumours. We are trying to understand cells manage to avoid this.For cells to divide correctly, they must copy their DNA and then separate each copy to opposite sides of the cell, so that when the cell divides into two, each new cell inherits one single copy of the DNA. The copied DNA is pulled apart by molecular "fibres" known as microtubules, and these fibres are formed by spherical objects known as centrosomes. The fibres reach out from one of two centrosomes positioned either side of the DNA and then attach and pull the copied DNA apart.Importantly, each daughter cell inherits only one centrosome, but needs two to be able to divide again. Thus, the centrosome must duplicate itself and this duplication process must not go wrong, as producing too many centrosomes can lead to problems when the cell tries to separate the duplicated DNA, and this may lead to cancer. Our key aim is to understand how centrosome duplication is properly controlled. Centrosomes are composed of a pair of cylindrical-shaped structures known as centrioles. During centrosome duplication, these centrioles split apart to produce two new centrosomes. To ensure that this can happen in the following cell cycle, each centriole must produce a new "daughter" centriole, resulting in a new pair of mother and daughter centrioles in each centrosome. Although under normal conditions only one new daughter centriole is produced during this process, it is possible that multiple daughter centrioles can form on a single mother centriole, and this ultimately results in too many centrosomes being made. Within the cell, centrosomes are tightly associated with a membrane that surrounds the DNA, known as the nuclear envelope. Unexpectedly, we have recently found that daughter centrioles tend to form on the side the mother centriole that faces the nuclear envelope, and when we artificially detach the centrosomes from the nuclear envelope the position of daughter centriole assembly on the mother is randomised. We want to investigate if the local environment between the mother centriole and the nuclear envelope drives daughter centriole assembly. We predict that this may help ensure that one and only one new daughter assembles during each centriole duplication event.We will test this using fruit flies as a model system, as we can easily manipulate their genome to create the ideal conditions for our experiments. Most of the genes in the fly are similar to our own and the process of centriole duplication is very similar in flies and humans. Therefore, what we discover in the fly will be of great importance to understanding human health and disease. We have also established a collaboration with a lab who works with human cell lines, and we will use the information we learn from the fly to investigate how cellular structures such as the nuclear envelope may influence and help control centriole duplication in human cells.