Ionizing Radiation, DNA Damage Response and Cancer Therapy Resistance

A frequently used treatement option in cancer is ionizing radiation. Unfortunately , therapy resistance occurs in the course of treatments. The work described in this thesis aims to elucidate the role of the DNA damage response in acquired resistance to ionizing radiation and its differential regulation upon DNA damage. Chapter 2 shows that different DNA repair pathways display redundancy in radiotherapy-resistant prostate cancer cells. Chapter 3 unravels the mRNA response in radiotherapy resistance using next generation sequencing to identify novel pathways. Energy metabolism was identified as one of the main contributors to radiotherapy resistance next to the DNA damage response. Chapter 4 presents the differential response of an important cell type, embryonic stem cells, to equitoxic dosages of three genotoxic agents. Based on mRNA and small RNA sequencing we were able to identify a novel posttranslational modification, citrullination, that is involved in the proper function of homologous recombination upon induction of double strand breaks (DSBs) in DNA in cancer cells. In Chapter 5 the role of RNA-binding proteins in DSB repair in cancer cells was investigated. Unexpectedly, we found that proper homologous recombination repair of DSB is dependent on RNA-binding proteins. However, the effect seen in RNA-binding protein knockdown is opposite discusses the implications of the differential response to DSBs in cancer cells.of the effect seen in Chapter 4. This indicates a tight regulation of DSB repair upon genotoxic stress. Chapter 6 summarizes the main results

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