Understanding DSB repair from pathway choice to long term effects and their consequences.

ongoing

DNA safekeeping is one of the most important functions of the cell. Since DNA damage occurs in the context of chromatin, it affects both the DNA itself, but also the epigenetic landscape. While the repair mechanism of the DNA has been extensively studied, questions abound regarding the restoration of the epigenetic landscape, and the long-term effects that damage leaves in the region. In this proposal I aim to address these questions using modified DSBs repair sensors from different pathways such as “homologous recombination” and “non-homologous end joining” to map the repair process. Our method will allow us to investigate the influence of the natural epigenetic landscape on pathway choice, the dynamic process of repair and the restoration of the region. Moreover, we will investigate whether certain repair processes leave long- lasting effects at the site of damage or even “epigenetic scars”. The advantage of our method is that it allows us to map each sensor repair time-line in an unbiased and high throughput manner over extended periods of time, even once the damage is already repaired. These questions are especially important for our understanding of ageing, and age-related diseases that are driven by DNA damage. Last, we will test the long-lasting effects of past damage in two different contexts: animal models of neurodegeneration, where DNA damage accumulates, and in the efficiency of reprograming to produce healthy induced pluripotent stem cells (IPCs).