TOXI 25 |
| ERCC1-XPF is an endonuclease essential for nucleotide excision repair (NER) of helix-distorting DNA adducts and the repair of DNA interstrand crosslink s (ICLs) via a distinct repair mechanism. Subtle mutations in XPF cause xeroderma pigmentosum, characterized by photosensitivity and increased risk of skin cancer. We identified a progeroid syndrome caused by a severe mutation in XPF, affecting nuclease expression. This was modeled in the mouse. ERCC1-XPF-deficient mice have a rapidly progressive progeria that mimics natural aging at the fundamental level of genome-wide expression changes, endocrine changes and pathophysiology. This provides strong evidence that unrepaired DNA damage promotes aging in mammals. Because the progeroid phenotype of ERCC1-XPF mutants is distinct from the phenotype of other NER mutants, we ascribe the accelerated aging to an inability to repair ICLs. The phenotype is also spontaneous. Therefore current efforts are aimed at identifying the endogenous lesions that promote accelerated aging in ERCC1-XPF-deficient mice.
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Frontiers in Chemical Toxicology
1:00 PM-4:45 PM, Monday, August 20, 2007 BCEC -- 258C, Oral
Division of Chemical Toxicology |