Control of repair activities at DNA double strand breaks and telomeres

The DNA in our cells, storing the information that every cell needs to perform its specific function, needs to be carefully protected. Various sources, both externally and from inside the cell, constantly threaten the integrity of the DNA, causing DNA damage. DNA double strand breaks (DSBs) are the most detrimental to the cell, and lack of repair, or incorrect repair of such breaks can lead to cell death. Moreover, incorrect repair can introduce errors in the DNA such as mutations or chromosomal rearrangements, resulting in genomic instability which can eventually contribute to the development of cancer. Cells have therefore developed mechanisms that detect the damage and ensure rapid and correct DNA repair, and this is collectively referred to as the ‘DNA damage response’. Importantly, the ends of natural chromosomes resemble DSBs, but repair activities at chromosome-ends would have severe consequences for genome integrity. The ends of chromosomes are therefore protected by specialized structures known as telomeres. The aim of this thesis is to increase our understanding of how repair activities at DSBs and telomeres are controlled. For this we used various methods aiming at identifying novel proteins that act in the DNA damage response and mechanistically understand their function.