Every human cell packs two metres of DNA into its nucleus, and that DNA must be both read to make proteins and copied to divide—without the two molecular machines crashing into each other. This project will map, for the first time at high resolution across the entire genome, exactly where the replication and transcription machineries sit on DNA at any moment. Until now, researchers had only blurry images showing the two processes occupy separate spaces, but lacked the tools to see precisely where. The team will create an open-access resource so other scientists can use these maps. They will also test whether a specific timing program that controls when DNA is copied is the mechanism that keeps transcription and replication apart. If that program fails, the two machineries collide, damaging the genome. Such collisions are already linked to neurodegenerative diseases and cancer. This is fundamental science—it will reveal a core biological principle that likely operates across all complex organisms. Understanding how cells normally avoid these conflicts could, in the long term, point toward new therapeutic strategies for diseases driven by genome instability.
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All the genetic information required to build a human is stored in 2m of DNA, in each cell of our body. The DNA is organised in thousands of functional units, the genes, many of which are constantly transcribed into RNA, to make proteins. The DNA also needs to be copied, or replicated, to grow a 37 trillion-cell human body from a single cell. How do DNA replication and transcription manage to coexist without interfering with each other? We hypothesise the existence of a mechanism separating the two processes in space and time to avoid the physical collision of the replication and transcription machineries. To test our hypothesis, the first step is to map exactly where the two machineries normally sit on the DNA, at any given time. Until recently, we did not have the necessary technical resolution to create a meaningful map and we had only very low-resolution imaging data that told us that the transcription and replication machineries are separated in space. The development in the last three years of new genome-wide approaches finally provides us with the tools to establish their exact location at high temporal and spatial resolution. We will therefore map the position of the replication forks and the transcription machinery and create an open resource to enable user-friendly access to our results. This will maximise the value of our research, extending it to the entire scientific community. Our preliminary data suggest that one specific pathway that controls DNA replication in time and space, the DNA replication-timing program, is implicated in maintaining transcription and replication separation. We will perturb this pathway and determine the effects on the reciprocal position of transcription and replication machineries at high resolution. Finally, it is already known that conflicts between transcription and replication destabilise the genome and can contribute to neurodegenerative diseases and cancer. We will establish if the cells where we have eliminated the DNA replication-timing program indeed undergo genome destabilisation due to transcription-replication conflicts. The significance of this project is therefore three-fold. Firstly, by leveraging the most recent technological developments, our results will enable for the first time a genome-wide integrated vision of transcription and replication. Secondly, we will reveal a key biological principle, discovering a molecular mechanism that preserves genome stability, potentially in all eukaryotes. Thirdly, our data will provide a new molecular understanding of the events that lead to genome instability, thus potentially paving the way to new therapeutic approaches in the future. Our proposal aligns therefore with objective 3.2 of the BBSRC strategic plan "Understanding the rules of life".
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