Genetic alterations such as mutations, genomic rearrangements and aneuploidy, are commonly observed in tumors. To counteract this cells have multiple genome maintenance and surveillance systems to... Show moreGenetic alterations such as mutations, genomic rearrangements and aneuploidy, are commonly observed in tumors. To counteract this cells have multiple genome maintenance and surveillance systems to minimize the rate at which genomic alterations arise. The aim of the thesis is to gain understanding of processes and pathways that contribute to the maintenance of genome stability and to establish how defects in these processes and pathways abrogate the DNA damage response and consequently may promote genomic instability and development of cancer. The work described in this thesis addresses various aspects of the cellular response of mammalian cells to DNA damaging agents including changes in post translational modifications that occur after genotoxic stress. The role of poly-adenosyl ribose modification in nucleotide excision repair is investigated and found to be important for the recruitment of a chromatin remodeling protein and repair. Phosphoproteomic analysis identified changes in the global phosphorylation state of proteins following genotoxic stress. Key kinases responding to DNA damage are ATR and related kinases. A detailed study into the requirements for ATR activation after UV exposure indicates that at least two distinct modes of activation exist. Finally we describe the profound sensitivity of Cornelia de Lange Syndrome cells to DNA damage. Show less
