Periodic Reporting for period 1 - RepliFate (DNA replication at the heart of cell fate decisions and cancer development)
Reporting period: 2022-10-01 to 2024-09-30
RepliFate is doctoral network designed to train the next generation of European researchers in the field of DNA replication, cell fate and cancer. We have designed an innovative training program that aims at providing interdisciplinary and intersectoral formation for the fellows. We base the network in inclusion, creativity and communication as the base to train the researchers in all aspects of scientific activity.
RepliFate investigates the mechanisms through which changes in DNA replication influence cell identity, respond to different kinds of stress, and prevent the development of cancer. We shift the paradigm in the field to place DNA replication at the center stage as the driver of cell identity and not a mere bystander. This approach paves the way for the development of innovative treatments by exploring the links between DNA replication and cell fate, the immune response and cancer. Thus, RepliFate contributes to the promotion of health and well-being in the European society. In particular we tackle Mission Cancer set on the Horizon Europe by contributing to the objectives Understand and Optimise in Mission Cancer. RepliFate is a meeting point of academia, industry and society to promote research in the field of DNA replication in health and disease.
RepliFate is composed by 10 European beneficiaries (9 from academia and 1 from industry) along with 2 Swiss associated partners (with their own funding from the Swiss government), 4 companies, 1 news agency and 2 non-profit organizations as associated partners from 8 different countries. We have created an outstanding training program to foster independent and out-of-the-box views in the fellows to train them as the future leaders in the field. RepliFate bridges basic and applied science to improve the resilience of the European society by positively impacting on our response to the huge health challenge constituted by Cancer.
RepliFate investigates the mechanisms through which changes in DNA replication influence cell identity, respond to different kinds of stress, and prevent the development of cancer. We shift the paradigm in the field to place DNA replication at the center stage as the driver of cell identity and not a mere bystander. This approach paves the way for the development of innovative treatments by exploring the links between DNA replication and cell fate, the immune response and cancer. Thus, RepliFate contributes to the promotion of health and well-being in the European society. In particular we tackle Mission Cancer set on the Horizon Europe by contributing to the objectives Understand and Optimise in Mission Cancer. RepliFate is a meeting point of academia, industry and society to promote research in the field of DNA replication in health and disease.
RepliFate is composed by 10 European beneficiaries (9 from academia and 1 from industry) along with 2 Swiss associated partners (with their own funding from the Swiss government), 4 companies, 1 news agency and 2 non-profit organizations as associated partners from 8 different countries. We have created an outstanding training program to foster independent and out-of-the-box views in the fellows to train them as the future leaders in the field. RepliFate bridges basic and applied science to improve the resilience of the European society by positively impacting on our response to the huge health challenge constituted by Cancer.
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.
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.
The fellows joined the groups during 2023, most of them around September and that is when the individual projects were launched. Thus, we do not expect to have significant advances beyond the state-of-art yet. As expected, we have developed the tools and systems required for the following steps in the different projects. We expect to obtain significant results in the next two years.