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of the detoxification proteins metallothionein-l and -2 genes, the expression of
which is enhanced by a great number of stimuli like heavy metal ions, reactive
oxygen intermediates and X-rays [37 and references therein]. MTF-l also regulates
expression of y-glutamylcysteine synthetase gene, a key enzyme in glutathion
biosynthesis, involved in radical scavenging. The clinical overlap between these
mouse mutants is currently only correlative and the role of DNA lesions in the onset
of each of the phenotypes has to be analyzed.
TTD, CS and the involvement in transcription
The extreme clinical heterogeneity associated with a NER defect cuhninates
particularly in XP complementation groups -B and -D. Mutations in the XPB and
XPD genes can give rise to XP, XP combined with CS or to TID features. A clue to
the intriguing diversity of symptoms came from the observation that XPB and XPD
are subunits of the protein complex TFIIH, which has a dual role in NER and basal
transcription initiation [29, 30]. The latter function is essential for all RNA
polymerase II mediated transcription. The XPB and XPD proteins are DNA
helicases [38] with opposite polarity (3'-->5' and 5'-->3' respectively) that endow
TFIIH with a bi-directional unwinding potential, required for local opening of the
promoter region in basal transcription and around the lesion in NER [39]. Because
the origin of growth retardation, skeletal abnormalities and neurodysmyelination in
CS and the additional brittle hair and ichthyosis symptoms in TID are difficult to
imagine via a NER defect, it was hypothesised that these non-XP features in CS and
TTD are due to an impairment of the transcription function of XPD or XPB,
whereas the photosensitivity is a consequence of affecting the repair function of
XPD or XPB [40, 41]. Non-photosensitive TTD patients can be rationalized by the
"repair/transcription-syndrome" model as a mutation that cripples the transcription
function of TFIIH but leaves the repair function intact. As expected, targeted
disruption of these essential genes in the mouse results in pre-implantation lethality,
and development is arrested probably as early as the two-cell stage when zygotic
transcription starts [7]. Moreover, mutation analysis of XPD in different patients
indicated that each causative mutation is syndrome-specific and mostly subtle
pointrnutations are found [42-45]. Introduction of a TID-specific point mutation in
the mouse XPD gene unequivocally demonstrated that the broad spectrum of
clinical symptoms in TID was due to this subtle defect. TID mice reflect to a
remarkable extent the pleiotropic features of the human disorder, including
reduction of hair-specific cysteine-rich matrix proteins (CRPs) resulting in brittle
hair, growth delay, reduced fertility and life span, and UV sensitivity (Figure 2).
NER-deficient mouse models 39