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INTRODUCTION
Genomic instability is an eminent feature in the progression of a normal somatic
cell into a transfOlmed cancer cell. To preserve DNA integrity, a network of
genome 'caretaking' mechanisms has evolved. An important component of this
protection system is a set of complementary DNA repair processes that safeguard
the genome from environmentally and endogenously induced mutagenic lesions.
The nucleotide excision repair (NER) system eliminates a wide diversity of
stlUcturally um-elated DNA lesions, including cyclobutane pyrimidine dimers and
(6-4) photoproducts (main DNA damage induced by UV-light), intrastrand
crosslinks, bulky chemical adducts and some fonns of oxidative damage (13),
making NER the most versatile DNA repair mechanism known to date. The NER
process involves the concerted action of approximately 30 proteins in subsequent
steps of damage recognition, local opening of the double helix around the injury and
incision of the damaged strand on either side of the lesion. After excision of the
damage-containing oligonucleotide, the resulting gap is filled by DNA repair
synthesis followed by strand ligation (13, 43). The importance ofNER is illustrated
by three rare, autosomal recessive human NER-deficiency syndromes: xerodelma
pigmentosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TID) (3).
XP patients, with a defect in one of the NER components (XPA-XPG), are very
sensitive to sunlight and have a -lOOO-fold increased risk of developing skin cancer.
In XP patients, the age of onset of non-melanoma skin tumors is reduced from 60 to
8 years of age (17). Additionally, pigmentation abnormalities in sunlight-exposed
areas are a hallmark feature and frequently accelerated neurodegeneration occurs
(reviewed in 3). CS is characterised by photosensitivity and several additional
symptoms, which are difficult to rationalise via a defect in NER, such as severe
growth retardation (referred to as cachectic dwarfism), neurodysmyelination and
skeletal abnOlmalities. On the basis of the progressive nature and resemblance to
aging phenotypes of several of these features, CS is recognized as a segmental
progeroid syndrome. A mutation in the CSA or CSB gene is associated with a
selective defect in transcription-coupled repair. This NER subpathway accomplishes
very efficient removal of transcription-obstructing lesions from the template strand
of active genes, which are less efficiently repaired by the complementary NER
process, global genome repair (GGR) (35). Remarkably, CS patients appear not
cancer-prone. Moreover, patients with combined features of XP and CS were
identified with defects in the XPB, XPD or XPG genes (6, 36, 42). Adding to the
clinical complexity, XPB and XPD are also involved in the photosensitive form of
the third NER syndrome: TTD (30, 41).
TTD shares many features with CS, including (neuro)developmental and skeletal
abnonnalities. In addition, TTD patients display ichthyosis (scaling of the skin) and
a specific defect in the expression of a group of cysteine-rich matrix proteins
underlying the striking brittle hairs and nails (14), the hallmark of the disease. TTD
88 Chapter 5