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[8, 9] reported substantial embryonic lethality, survivors are extremely mnted and
die before weaning but some live up to 6 months of age (Figure 1). A number of the
features point to premature aging. Death resulted from severe progressive liver and
kidney dysfunction associated with early onset of polyploidization and aging-related
nuclear abnonnalities (such as inclusion bodies) in cells of these organs. Mutant
mice displayed absence of subcutaneous fat and ferritin deposition in the spleen.
Though elevated levels of p53 staining was seen in a fraction of cells in liver,
kidney and brain of EReCl mice, no indication for increased apoptosis was found.
Comparing the ERCCI-/- mice with other NER-deficient mutants suggests that
endogenous lesions are generated in the liver which are a substrate for ERCCl, but
not for other NER components because none of the other NER mice display this
phenotype. The involvement of defective cross-link repair is consistent with the idea
that accumulation of interstrand cross links contributes to the observed phenotype. A
candidate agent could be malondialdehyde, a by-product of fatty-acid metabolism
that induces intrastrand crosslinks [35]; other types of DNA lesions may be
involved too, such as oxidative lesions. The phenotype ofERCCI mice may provide
clues to a possible human syndrome associated with a severe defect in the
ERCClIXPF functions. Besides ERCCl, several other mouse models exist in which
aberrant function of effectors to DNA damage leads to liver dysfunction. First, a
mouse model was established with hepatocyte-specific targeted expression of the
cyclin-dependent kinase inhibitor p2l [36], involved in DNA damage-induced G,arrest.
Figure 1. Phenotype
of EReCt mutant
mice. Photograph of a
3-4 week old homozygous
wild-type
mouse (back) and it's
littermate, which is
homozy-gous for the
truncating ERCCl·}tJ:!
alJeJe (front). The
ERCCI mutation
causes runted growth,
reduced life span and
premature senescence
of cultured fibroblasts
[8].
This resulted in halting of hepatocyte cell cycle progression, resulting in ERCCI
knockout-like polyploid cells in liver, mnted body growth and increased mortality.
Secondly) XPA mice develop spontaneous liver tumors) indicative of high
genotoxic stress in the liver [26]. Furthermore, embryonic lethality and liver
degeneration is observed in mice lacking the transcription factor MTF-l [37]. MTF-
1 is thought to playa general role in cellular stress response. It regulates expression
38 Chapter 2