Determining how transcription and replication are coordinated during S-phase

RNA Pol II transcription and DNA replication are the two essential processes that use the DNA in our cells as a substrate. However, DNA can be engaged only by one of these processes at any given time, and when transcription impairs DNA replication it can induce DNA damage and genome instability. We have shown that transcription activity is transiently reduced to support the replication of genes. We have also identified two separate mechanisms that cells use to regulate transcription activity, that occur in different moments during S-phase transcription and involve separate regulatory mechanisms. Interestingly, one of these occurs only on genes in proximity of the replication fork in early S-phase and alters transcription regulation for several hours. Importantly, both depend on the activity of essential DNA damage checkpoint kinases.

Aims of the project:

We are now interested in investigating how cells regulate transcription activity, using a combination of genome-wide and functional assays:

i) Identifying targets and mechanisms through which cells regulate in a timely manner transcription activity as replication forks progress through the genome.

ii) Determining the consequences for genome stability from the lack of regulation of transcription activity when genes are replicated.

iii) Defining the global impact on transcription activity and chromatin re-establishment if transcription is not properly regulated.