RepliFate’s scientific objectives are organized in four main blocks: Understand, Drive, Respond and Target. These blocks address different aspects with the overarching objective of exploring how DNA replication influences cell identity, response to stress and cancer. In most cases, the fellows have been working in the groups for less than 1 year. Up to now we have carried out mostly preliminary studies and experiments to establish the systems to study the specific questions that we want to address in the next two years.
Within Understand we have made progress in the identification of new substrates of E3 ubiquitin ligases involved in the control of DNA replication and genome stability. Further, we are working on the purification of enzymes of the ubiquitin pathway with functions in DNA replication to carry out structure-function studies of these enzymes. Finally, we are also analyzing how blocking DNA replication is sensed by the replication stress response leading to the activation of specific responses to maintain genome stability.
Drive deals with the changes in DNA replication related to cell identity. We are interested in understanding how the replication machinery changes in different chromatin environments using multiple cellular models in specific chromatin contexts. In addition, we are exploring the roles of DNA replication in cell fate decision by studying the primed-to-naïve transition in mouse embryonic stem cells, as well as the totipotency-multipotency transition in embryonic development. We focus on enzymes that control chromatin structure during DNA replication and in regulatory regions in our genome with a potential role in the process.
In Respond we tackle how the changes in DNA replication are connected to the inflammatory response and the malignant transformation. We are studying the release of nuclear DNA to the cytoplasm and the activation of the inflammatory response induced by this DNA. To that end we are generating cellular models where alterations in DNA replication induce the release of nuclear DNA and we are analysing how the inflammatory response contributes to cell fitness in cancer models that also present higher levels of cytosolic DNA.
Target has the objective of developing assays and identifying drugs against new potential targets in cancer treatment. To achieve this goal, we are establishing new cellular and mouse cancer models using candidate genes involved in colon cancer generation. In addition, we are generating new cellular models deficient in DNA repair pathways to conduct CRISPR screenings to identify synthetic lethal interactions in these DNA repair pathways. Finally, we are setting up the conditions to screen for drugs targeting different proteins involved in the maintenance of genome stability.
