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patients have a reduced life expectancy, but extensive clinical heterogeneity exists,
ranging from mild growth retardation to life-threatening cachexia. Just like CS,
TTD appears to be not associated with skin cancer predisposition despite the overt
NER defect. Moreover, although considerable heterogeneity in severity of the NER
defect is seen (18, 29), no clear correlation exists between severeness of many TTD
features and the DNA repair defect. In fact, a subgroup of non-photosensitive, NERproficient
TTD patients is also known, suggesting that the NER impairment and the
typical TID phenotypes are clinically and perhaps molecularly umelated. In support
of this idea, it was discovered that XPB and XPD are essential DNA helicase
subunits of the dually functional DNA repair/basal transcription initiation factor
TFIIH (26, 27). Previously, we proposed that mutations in those genes may not only
affect NER, causing XP and the photosensitivity in CS and TTD, but depending on
the mutation may also subtly impair basal transcription explaining the typical CS
and TTD features (15, 38). Consistent with this hypothesis, mutation analysis of
XPD in different patients indicated that each causative mutation is syndromespecific
(4, 5, 31-33). Mostly subtle point mutations are found, consistent with the
essential role of XPD in basal h'anscription initiation, Moreover, by gene targeting
we showed that a XPD null allele is lethal in mice, in a very early stage of
embryogenesis (8).
To study the complex clinical symptoms and the paradoxical absence of skin
cancer in NER-deficient TID patients, we generated a mouse model for TID by
mimicking the XPDR722W allele in the mouse gennline as found in five TID patients
(7). TID mice reflect to a remarkable extent the pleiotropic features of the human
disorder, including growth delay, reduced fertility and life span, cutaneous
abnormalities and UV sensitivity of cultured fibroblasts. Like in patients, TTD mice
displayed the remarkable brittle hair phenotype due to a reduction of hair-specific
cysteine-rich matrix proteins, Moreover, we found that the keratinization defect in
TID mice is associated with reduced transcription of the late telminal
differentiation marker SPRR2, consistent with the idea that reduced transcription
potential explains part of the TID features. Having established a valid mouse model
for TTD, this paper presents further characterization of the repair defect of TID
mice, and examines the crucial issue of cancer predisposition,
RESULTS
Repair characteristics and genotoxic sensitivity of NER-deficient cells
To provide a detailed account of the DNA repair defect in the TID mouse model at
the cellular and organisrnal level a number of DNA repair parameters was
systematically examined and compared with DNA repair characteristics of other
NER-deficient mouse mutants. We first studied repair parameters in primary mouse
TID mice reveal cancer-predisposition 89