DNA damage has been implicated as a causal factor of cancer development and is thought to contribute to aging. The effect of DNA damage both in cancer and aging becomes particularly apparent in patients that are defective in nucleotide excision repair (NER). NER comprises two distinct branches that differ in the initial damage recognition and lead to distinct clinical outcomes. Global genome (GG) NER recognizes damages throughout the genome, whereas transcription-coupled repair (TCR) specifically removes damage during transcription. GG-NER deficiencies lead to the skin cancer susceptibility syndromes xeroderma pigmentosum (XP) whereas TCR deficiencies lead to progeroid conditions Cockayne syndrome (CS), trichothiodystrophy (TTD) and XPF-ERCC1 progeria (XFE). Recently, we have identified specific cellular response programs to persistent transcription-blocking lesions. We showed that persistent transcription-blocking lesions lead to attenuation of IGF-1R and GHR resulting in cellular IGF-1 resistance. IGF-1R and GHR are central regulators of somatic growth and their attenuation leads to extended longevity and stress resistance. IGF-1R has been shown to act as oncogene and pharmaceutical interventions targeting IGF-1R are in advanced clinical trials for cancer treatment. We have found that, in contrast to cells from tumor prone XP mice, primary cells from progeroid CS or XFE mouse models induce a prolonged IGF-1R and GHR attenuation. We proposed that somatotropic attenuation might be the critical determent of the progeroid but tumor free outcome of TCR deficiencies and the tumor prone outcome of GG-NER deficiencies. In this proposal we aim at investigating genetic interactions of skin cancer models of XP and IGF-1R knockout mutants. We thus aim at investigating tumor suppression strategies in skin cancer models to gain novel insights into the biology of skin cancer development and the biology of aging as well as giving rise to novel anti-cancer treatment strategies.
Field of science
- /natural sciences/biological sciences/genetics and heredity/genome
- /natural sciences/biological sciences/genetics and heredity/dna
- /medical and health sciences/clinical medicine/cancer/skin cancer
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