Correction of liver dysfunction in DNA repair-deficient mice with an ERCC1 transgene

The ERCC1 gene is essential for the repair of UV-induced DNA damage. Unlike most genes in the: nucleotide excision repair (NER) pathway, ERCC1 is: also involved in recombinational repair. Perhaps ford this reason, ERCC1 knockout mice are not a model for the human NER deficiency disorder, xeroderma: pigmentosum. Instead, ERCC1 null mice are severely, runted and die before weaning from liver failure with accelerated hepatocyte polyploidy that is more reminiscent of a premature ageing disorder. To permit study of the role of ERCC1 in other tissues we have corrected the liver ERCC1 deficiency with a transgene under the control of a liver-specific promoter. The transgene alleviated runting and extended the lifespan. The elevated level of oxidative DNA damage and premature liver polyploidly were reversed and liver function was corrected. A widespread mitochondrial dysfunction was identified and an essential role for ERCC1 in the kidney was also revealed with transgene-containing ERCC1-deficient animals going on to die of renal failure. The nuclei of kidney proximal tubule cells became polyploid in a similar way to the premature liver polyploidly observed in younger ERCC1-deficient animals. We believe that this is a response to the accumulation of endogenous DNA damage in these particularly susceptible tissues which cannot be repaired in ERCC1-deficient animals.