Embryonic stem cells (ESCs) have opened the way to the development of regenerative medicine
(cell therapy). For obvious reasons, preserving the integrity of their genome to avoid cancer
formation is of utmost importance. One possible cause for DNA damage is stress that occurs during
DNA replication (replicative stress). Interestingly, molecular evidence for this process has been
detected in both embryonic stem cells as embryonic cancer cells, pointing at a thin line between the
normal stem cells and these immature cancer cells. In this project, we will first perform in depth
genomic profiling of a newly established more representative type of ESCs, so-called naïve stem
cells. Next, we will further investigate the role of replicative stress as inducer of DNA damage in
ESCs. In parallel, we will also investigate the role of replicative stress induced DNA damage response
signaling as a cause for chemotherapy resistance and druggable target. To this end, we will develop
several novel innovative cellular model systems. In particular, normal ESCs will be used to generate
the normal progenitor cells of the immature cancer cells and subsequently genetically modulate
using new genome editing technology to model cancer formation. Finally, we selected five
candidate genes which will be functionally analyzed in relation to their role in replicative stress.