Cockayne Syndrome Mouse Models: linking impaired DNA repair and premature aging

DNA damage can be deleterious to both cells as well as the entire organism. Thus, it is of vital importance that the genome is protected from genotoxic insults. Unrepaired DNA damage can interfere with cellular key processes like transcription and replication, resulting in cell death by apoptosis, and growth arrest or they induce mutations that ultimately may result in the onset of cancer (see (Hoeijmakers, 2001)). Accumulation of DNA damage has also proposed to be a major contributor to age-related diseases (e.g. (Hasty et al., 2003; Mitchell et al., 2003)). This is demonstrated by Cockayne Syndrome (CS), an inherited progeroid disorder, which is caused by a defect in the transcription coupled repair subpathway of nucleotide excision repair (TC-NER) CS is characterized by UV-sensitivity of the skin, progressive growth failure, together with many neurological symptoms. CS is recognized as a “segmental” progeroid syndrome, as evident from the observation that patients show early onset of a subset, but not all features of normal aging. No cure is available for this disease other than treatment of the symptoms that present themselves. In this thesis we set out to investigate the underlying mechanism that results in the very severe progeroid phenotype observed in CS by use of existing and new mouse models.