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Repair and regulation in DNA damage response

Carlsberg Foundation Reintegration Fellowships

What

This project investigates how living cells handles the occurrence of DNA breaks. In general, damage of DNA is unavoidable, and therefore it is crucial that living organisms ensures that this is not inherited through cellular generations. In this process, two of the most important elements is the physical repair of sites carrying breaks, and the regulation of cell state that ensures that cells do not pass new mutations down through generations. A key element of the repair process is the formation of small sub-compartments known as foci and in this project we will investigate how these structures can affect the concentration dynamics of important regulatory proteins, especially the extremely important transcription factor p53.

Why

The fundamental mechanisms of DNA repair have long been separated from the following regulation of transcription factors, and it is the main goal of this project to bridge these fields in order to establish a holistic picture of how living cells deal with DNA damage. It is well known that damage of DNA, introduces a broad cascade of pathways, but why the important transcription factor p53 start to shown oscillatory concentration dynamics is still not known. The link between this fingerprint in p53 behaviour, with the sudden creation of multiple foci has not been fully investigated, and thereby this project can enhance our understanding of cellular response and why this breaks down when cells pass on damaged DNA.

How

I will combine the theoretical knowledge of spatiotemporal signaling and biological networks with experimental results on p53 regulation and DNA repair proteins in order to create mathematical models that can predict the relation between foci formation and p53 concentration dynamics. Through this, we can obtain a deeper understanding of the underlying mechanisms in signaling between DNA repair and regulation. I have previously worked with p53 regulation at Harvard Medical School, and with the physical principles of DNA repair at Ecole Normale Superieure. In collaboration with experimentalists at both institutions, I will examine the link between DNA repair and regulation, and with this grant, I can pursue this fundamental idea of combining these areas.

SSR

The outbreak of cancer is a major challenges to human society and understanding this is one of the scientific questions that could benefit modern society significantly. Even though the term cancer covers a broad range of diseases, a common feature is that mutations, that under normal conditions had been repaired, has been passed on through cellular generations, and in the caused uncontrolled division. Therefore, a fundamental task is to understand how cells normally ensure that these mutations are not inherited through generations and in this regard it is of particular importance that the DNA damage is both properly repaired and not passed on. This project has the potential to explain a cornerstone of this process, and with new knowledge in this field, it might be possible to find patients that are vulnerable to cancer and an earlier stage. Furthermore, understanding how repair affect the concentration of p53, could be used in future cancer diagnosis strategies.