Elucidating the role of the nuclear envelope in centriole duplication

我们的身体是由数十亿个细胞组成的，但我们最初只有一个受精卵，它分裂成两个，然后是四个，然后是八个细胞，等等。一旦这些细胞成为一个正常运作的有机体，许多细胞继续分裂，帮助重新生成受损的组织。有时细胞分裂出错，细胞分裂失控，产生癌性肿瘤。我们正在试图理解细胞设法避免这种情况。为了细胞正确分裂，它们必须复制自己的DNA，然后将每个拷贝分离到细胞的两边，这样当细胞分裂成两个时，每个新细胞继承一个单一的DNA拷贝。复制的DNA被称为微管的分子“纤维”拉开，而这些纤维是由称为中心体的球形物体形成的。这些纤维从位于DNA两侧的两个中心体中的一个伸出，然后连接并拉动复制的DNA片段。重要的是，每个子细胞只继承一个中心体，但需要两个中心体才能再次分裂。因此，中心体必须自我复制，这种复制过程不能出错，因为当细胞试图分离复制的DNA时，产生太多的中心体可能会导致问题，这可能会导致癌症。我们的主要目标是了解中心体复制是如何被适当控制的。中心体由一对被称为中心粒的圆柱形结构组成。在中心体复制过程中，这些中心粒分裂，产生两个新的中心体。为了确保这可以在接下来的细胞周期中发生，每个中心粒必须产生一个新的“女儿”中心粒，从而在每个中心体中产生一对新的母女中心粒。虽然在正常情况下，在这个过程中只会产生一个新的女儿中心粒，但也有可能在一个母中心粒上形成多个女儿中心粒，这最终导致产生太多的中心体。在细胞内，中心体与DNA周围的一层膜紧密相连，这层膜被称为核膜。出乎意料的是，我们最近发现，女儿的中心粒往往形成在面对核膜的母亲中心粒的一侧，当我们人为地将中心粒从核膜上分离出来时，女儿中心粒在母亲身上的组装位置是随机的。我们想要调查母中心粒和核膜之间的局部环境是否驱动了女儿中心粒的组装。我们预测，这可能有助于确保在每个中心粒复制事件中都会有一个且只有一个新的子代组装。我们将使用果蝇作为模型系统来测试这一点，因为我们可以很容易地操纵它们的基因组，为我们的实验创造理想的条件。果蝇中的大多数基因与我们自己的相似，中心粒复制的过程在果蝇和人类中非常相似。因此，我们在苍蝇身上的发现将对了解人类健康和疾病具有重要意义。我们还与一个研究人类细胞系的实验室建立了合作关系，我们将利用从苍蝇身上学到的信息来研究核膜等细胞结构如何影响和帮助控制人类细胞中的中心粒复制。

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.