REPTIMORG · DNA replication timing and spatial organization of chromatin

DNA replication timing and spatial organization of chromatin

DNA replication is the essential process that ensures a correct duplication of the DNA before each cell division. This is a highly organised process in both space in time. It is known that all DNA within the cell is not replicated simultaneously, instead some regions are replicated earlier than others. The reason behind this temporal control of replication is not entirely clear but unscheduled replication is a common feature of cancer and malignant cells, highlighting the importance of an understanding of how the timing is regulated. Further, it is commonly known that the DNA is not randomly distributed within the nucleus. Instead, some regions are always positioned close to the periphery of the nucleus while other regions are more in the centre. Regions that are close to the nuclear periphery tend to replicate late while regions towards the centre replicate early. This is suggesting that the organisation of the DNA within the cell could play a role in the regulation of the replication timing. We have previously identified the protein Rif1 as a regulator of the temporal order of replication. But Rif1 is a complex protein with functions also in controlling higher-order DNA structures. My aim has been to understand if these two functions of Rif1 can be uncoupled or if Rif1 through just one single mechanism is controlling both. My research has also focused on the role of the nuclear periphery and the spatial organisation of DNA, in replication timing control, independently on Rif1. My studies show that Rif1 controls when certain regions are replicated while also positioning these regions to the nuclear periphery. We find that regions that replicate late, independently of Rif1 maintain their peripheral localisation also after Rif1 is removed. Together this suggests that, at least for the regions analysed, replication timing and nuclear positioning cannot be uncoupled. Females have two X chromosomes compared to males who have only one. To deal with this chromosomal imbalance between the sexes, nature has developed a system in which one of the two X chromosomes in mammalian female cells is being silenced. This means that the vast majority of genes on this chromosome become inactive, in other words repressed. The silencing of an X chromosome is carried out in a complex process, commonly known as the X-chromosome inactivation process. This process takes place very early during embryonic development, in mice as well as in humans, and it is absolutely crucial for the development of the female embryo. We find that mouse embryos that lack Rif1 die as a consequence of an inability to perform X-chromosome inactivation. I have been studying the process of X-chromosome inactivation in cells and the effect of removing Rif1, aiming at understanding the mechanism behind Rif1’s role in this fundamental process. My studies show that Rif1 plays a key role in the very first initiating steps and without Rif1, this whole process is blocked.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз