title: Disruption of mouse ERCC1 results in a novel repair syndrome with growth failure, nuclear abnormalities and senescence.
abstract: BACKGROUND
  The structure-specific ERCC1/XPF endonuclease complex that contains the ERCC1 and XPF subunits is implicated in the repair of two distinct types of lesions in DNA: nucleotide excision repair (NER) for ultraviolet-induced lesions and bulky chemical adducts; and recombination repair of the very genotoxic interstrand cross-links.
  
  
  RESULTS
  Here, we present a detailed analysis of two types of mice with mutations in ERCC1, one in which the gene is 'knocked out', and one in which the encoded protein contains a seven amino-acid carboxy-terminal truncation. In addition to the previously reported symptoms of severe runting, abnormalities of liver nuclei and greatly reduced lifespan (which appeared less severe in the truncation mutant), both types of ERCC1-mutant mouse exhibited an absence of subcutaneous fat, early onset of ferritin deposition in the spleen, kidney malfunction, gross abnormalities of ploidy and cytoplasmic invaginations in nuclei of liver and kidney, and compromised NER and cross-link repair. We also found that heterozygosity for ERCC1 mutations did not appear to provide a selective advantage for chemically induced tumorigenesis. An important clue to the cause of the very severe ERCC1-mutant phenotypes is our finding that ERCC1-mutant cells undergo premature replicative senescence, unlike cells from mice with a defect only in NER.
  
  
  CONCLUSIONS
  Our results strongly suggest that the accumulation in ERCC1-mutant mice of endogenously generated DNA interstrand cross-links, which are normally repaired by ERCC1-dependent recombination repair, underlies both the early onset of cell cycle arrest and polyploidy in the liver and kidney. Thus, our work provides an insight into the molecular basis of ageing and highlights the role of ERCC1 and interstrand DNA cross-links.
authors.affiliation: Department of Cell Biology and Genetics, Medical Genetics Center, Erasmus University, Rotterdam P.O. Box 1738, 3000 DR, Rotterdam, The Netherlands.
authors.forename: G
authors.initials: G
authors.lastname: Weeda
authors.forename: I
authors.initials: I
authors.lastname: Donker
authors.forename: J
authors.initials: J
authors.lastname: de Wit
authors.forename: H
authors.initials: H
authors.lastname: Morreau
authors.forename: R
authors.initials: R
authors.lastname: Janssens
authors.forename: C J
authors.initials: CJ
authors.lastname: Vissers
authors.forename: A
authors.initials: A
authors.lastname: Nigg
authors.forename: H
authors.initials: H
authors.lastname: van Steeg
authors.forename: D
authors.initials: D
authors.lastname: Bootsma
authors.forename: J H
authors.initials: JH
authors.lastname: Hoeijmakers
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D000375:Aging / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D002453:Cell Cycle; D002467:Cell Nucleus / Q000473:pathology; D002470:Cell Survival; D002478:Cells, Cultured; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004720:Endonucleases / Q000235:genetics*; D005347:Fibroblasts / Q000166:cytology / Q000473:pathology; D006130:Growth Disorders / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007668:Kidney / Q000002:abnormalities; D008099:Liver / Q000002:abnormalities; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009153:Mutagens / Q000494:pharmacology; D009154:Mutation; D011123:Polyploidy; D011506:Proteins / Q000235:genetics*; D013577:Syndrome
chemical_list: D004268:DNA-Binding Proteins; D009153:Mutagens; D011506:Proteins; C071447:ERCC1 protein, human; D004720:Endonucleases; C499360:Ercc1 protein, mouse