DISRUPTION OF MOUSE ERCC1 RESULTS IN A NOVEL REPAIR SYNDROME WITH GROWTH FAILURE, NUCLEAR ABNORMALITIES AND SENESCENCE

Background: The structure-specific ERCC1/XPF endonuclease complex that contains the ERCC1 and XPF subunits is implicated in the repair of tw o distinct types of lesions in DNA: nucleotide excision repair (NER) f or ultraviolet-induced lesions and bulky chemical adducts; and recombi nation repair of the very genotoxic interstrand cross-links. Results: Here, we present a detailed analysis of two types of mice with mutatio ns in ERCC1, one in which the gene is 'knocked out', and one in which the encoded protein contains a seven amino-acid carboxy-terminal trunc ation. In addition to the previously reported symptoms of severe runti ng, abnormalities of liver nuclei and greatly reduced lifespan (which appeared less severe in the truncation mutant), both types of ERCC1-mu tant mouse exhibited an absence of subcutaneous fat, early onset of fe rritin deposition in the spleen, kidney malfunction, gross abnormaliti es of ploidy and cytoplasmic invaginations in nuclei of liver and kidn ey, and compromised NER and cross-link repair. We also found that hete rozygosity for ERCC1 mutations did not appear to provide a selective a dvantage for chemically induced tumorigenesis. An important clue to th e cause of the very severe ERCC1-mutant phenotypes is our finding that ERCC1-mutant cells undergo premature replicative senescence, unlike c ells from mice with a defect only in NER. Conclusions: Our results str ongly suggest that the accumulation in ERCC1-mutant mice of endogenous ly generated DNA interstrand cross-links, which are normally repaired by ERCC1-dependent recombination repair, underlies both the early onse t of cell cycle arrest and polyploidy in the liver and kidney. Thus, o ur work provides an insight into the molecular basis of ageing and hig hlights the role of ERCC1 and interstrand DNA cross-links.