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INTRODUCTION
To counteract the deleterious effects of mutagenic and. carcinogenic agents, organisms
are equipped. with a sophisticated network of DNA repair systems. Nucleotide excision
repair (NER), one of the best studied DNA repair pathways, removes a wide diversity
of lesions, including cyclobutane pyrimidine dimers and (6-4) photoproducts (induced
by VV-light), as well as numerous chemical adducts. The consequences of inborn
errors in NER are highlighted by the rare autosomal recessive repair syndromes
xeroderma pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy
(TID). Complementation tests by cell fusion have demonstrated that the NER
syndromes are genetically heterogeneous and. comprise at least 10 complementation
groups: 7 in XP (XP-A to XP-G), 2 in the classical form of CS (CS-A and -B) and one
ill TID (TID-A), whereas two TID complementation groups are simultaneously XP
groups (XP-B and XP-D) (I, for a recent review).
XP patients display sunsensitivity, pigmentation abuOlmalities in sun-exposed areas,
frequently accelerated neurodegeneration and are predisposed to develop skin cancer.
The halhnarks of CS are sunsensitivity, severe mental and physical retardation, skeletal
abnonnalities and a wizened facial appearance. The mental dysfunction in CS is due to
lleurodysmyelination (2). In XP complementation groups B, -D and -G, some patients
show combined features of XP and CS. TID is characterized by sulphur-deficient
brittle hair and nails, ichthyotic skin, as well as impaired growth and
lleurodysmyelination like in CS (3). Moreover, approximately 70% of the TID patients
show a NER defect that in most cases is caused by mutations in the XPD gene
(previously referred to as ERCC2) (4, 5). Remarkably, CS patients as well as TTD
patients with a defect in NER are not cancerprone.
XPD was found to be identical to the p80 subunit of basal transcription factor TFIIH,
involved in transcription initiation of RNA pol II transcribed genes (6). Furthermore,
microinjection of the purified TFIIH complex into fibroblasts of other XP, XP/CS and
TID patients appeared to induce selective correction of the NER defect of XP
complementation groups Band -D and of TID complementation group A, but not of
the other XP groups (7). Most likely, TFIIH is involved in local unwinding of the DNA
duplex at the site of the DNA damage in the NER reaction and of the promoter in
transcription initiation, executed by the DNA-dependent ATPase and DNA helicase
activities associated with XPB and XPD (7, 8). Although most of the XP features can
be explained on the basis of a NER deficiency, a number of symptoms of CS and TTD
(such as the neurodysmyelination and the reduced content of cysteine-rich matrix
proteins in the brittle TID hair) are difficult to rationalize in tenns of a NER
impairment. The association of CS and TID phenotypes with mutations in the dually
functional TFIIH has led to the hypothesis that the unusual symptoms of these diseases
are due to subtle impainnent of the transcription function of the con·esponding proteins,
leading to transcription insufficiencies for genes involved in the CS and TID
symptoms. This 'repair/transcription-syndrome' concept also provides a rational for
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