DNA Repair and Genomic Instability in Cancer Development and Therapy

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 DESCRIPTION (provided by applicant): Most, if not all tumor cells harbor signs of genomic instability, which can contribute to their development. DNA repair combats genomic instability and thus, is a powerful tumor suppressor mechanism. Inherited mutations in genes encoding for repair factors are associated with significant increases in cancer susceptibility, establishing tha failure to repair DNA damage causes or facilitates tumor development. Nonetheless, DNA damaging therapies are amongst the most widely used and most successful cancer therapies. The inherent genomic instability of cancer cells makes them more vulnerable to a high damage burden. This can be exploited in the clinic by targeting specific DNA repair modules that are uniquely essential for tumor cells. We will build a map of protein-protein interactions for repair factors common to multiple repair pathways. We will identify protein-protein interactions, which are specifically enhanced or reduced following treatment with DNA topoisomerase inhibitors and DNA crosslinkers. These differentially regulated modules will identify potential vulnerabilities in the DNA repair networks of cancer cells and will open the possibility for precise, targeted therapies.