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Towards a systems level understanding of responses to endogenous DNA damage in Caenorhabditis elegans

Tildelt: kr 6,0 mill.

The impact of genomic instability on human health underscores the importance of understanding the mechanisms that coordinate responses to DNA damage in order to preserve genomic stability. There is a disparity between our knowledge of the cellular respons es to endogenous DNA damage and the impact they have on human health and disease. This is addressed here in novel approaches to study DNA damage responses and the functional consequences of accumulating DNA damage in Caenorhabditis elegans. We have deve loped molecular tools that allow us to describe the contribution of endogenous DNA damage to disease and aging in appropriately designed strains. We apply genome-wide approaches such as RNAi screens, global expression profiling and proteomics and integrat e the complex data-sets by computational methods to identify novel component of the DNA damage response. Existing mathematical algorithms for BER will be used to functionally validate predictions for consequences of specific alterations in repair capaci ty by monitoring phenotypic outcomes in large populations over their entire lifespan, based on kinetic data. This represents a first step towards generating a systems model for base excision repair and responses to oxidative DNA damage in animals. C. el egans can bridge the gap between in vitro and in vivo studies and we will perform and integrate data from reverse chemical genetics, expression profiling, and proteomics to determine how DNA damage and repair contribute to toxicity of anti-cancer drugs. The approaches present functional genomics in an animal which has yet to be exploited in Norway. This technology, with low running costs and high experimental strength, can be developed into a national resource, thus strengthening functional genomics. The se ambitions projects contribute significantly to our understanding of how defects in cellular responses to DNA damage might contribute to human cancer and aging and improve treatment and management of cancer.

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FUGE-Funksjonell genomforskn.i Norg