Interplay between RNA Pol II transcription and DNA replication

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RNA Pol II transcription is the process that generates copies of the genes in our genome, that are mainly used as a template for the production of proteins in cells, allowing them to express the factors that characterise their cellular identity; DNA replication is the process through which a cell duplicates its genome, generating two identical copies to pass on to daughter cells. They are therefore by definition both essential processes that any living cell at some point in their life will find doing together. However, we know that transcription and replication can interfere with each other affecting their functions, and ultimately inducing DNA damage and genome instability. This is a fundamental biological question in cell biology, for which we have no clear understanding, and that has direct consequences for cell growth as well as human health. Nevertheless, the complete interplay between RNA Pol II transcription and DNA replication is actually so far unknown. In order therefore to determine how transcription and replication are organised in the genome to avoid negative consequences for genome stability, we have analysed both processes at the same time during cell cycle progression. We have so uncovered how and where transcription and replication affect each other. We found that when replication passes through a transcribed gene it reduces temporally transcription activity; transcription vice versa affects replication progression through genes; we also found that difficult to replicate regions in transcribed genes have their replication delayed compared to the surrounding area, postponed to later stages in cell cycle progression. All together we have uncovered so far, the first description on how these two processes are coordinated and how exactly they affect each other, at the genome wide level, identifying key molecular processes that are crucial for this relationship. In our proposal we are now going to characterise in greater detail the molecular mechanisms regulating the interplay between transcription and replication. We will determine how transcription regulates DNA replication progression inside genes but also how it affects the choice of where DNA replication starts, called DNA replication origins. We will determine how maintaining the RNA Pol II around transcription start sites might be important to keep a signpost of where these sites are in the vastity of the genome, although this means delaying DNA synthesis across them to a later moment in the cell cycle; we will also determine which pathways regulate this DNA synthesis. Moreover, we will analyse the impact on genome stability that comes as cost of this interplay. Altogether, we intend dissecting the interplay between RNA Pol II transcription and DNA replication to a level so far never achieved.