View PDF Version - RePub - Erasmus Universiteit Rotterdam

SUMMARY AND CONCLUSIONS
DNA damage is implicated in cancer and aging, and several DNA repair
mechanisms exist that safeguard the genome from these deleterious consequences.
Nucleotide excision repair (NER) removes a wide diversity of lesions, among which
the main UV -induced lesions, bulky chemical adducts and some fOlTI1S of oxidative
damage. The NER process involves the action of at least 30 proteins in subsequent
steps of damage recognition, local opening of the DNA 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 fined by
DNA repair synthesis followed by sh·and ligation. The consequences of a defect in
one of the NER proteins are apparent from three rare recessive syndromes:
xeroderma pigmentosum (XP), Cockayne syndrome (CS) and the photosensitive
fotTIl of the brittle hair disorder trichofuiodystrophy (TID). Sun-sensitive skin is
associated with skin cancer predisposition in the case of XP, but remarkably not in
CS and TTD. Moreover, the spectrum of clinical symptoms differs considerably
between the three syndromes. CS and TID patients exhibit a spech·um of
neurodeve1opmental abnOlIDalities and in addition, TrD is associated with
ichfuyosis and brittle hair. These typical CS and TTD abnormalities are difficult to
comprehend as a consequence of defective NER. The involvement of certain NER
proteins in the process of transcription suggests that impaired transcription may
underlie the non-NER features of CS and TTD.
Chapter 1 provides a review of the molecular mechanism of NER, the genes
encoding the different repair proteins, and the clinical consequences of a defect in
NER. Several transgenic NER -deficient mouse models have been generated in
recent years, and Chapter 2 summarizes the literature on mouse experiments
focusing on the role of NER in mutagenesis and carcinogenesis. Importantly,
several NER proteins have a dual involvement in NER and other cellular processes
like transcription or mitotic recombination. The phenotypic consequence of a defect
in these other processes in the mouse is discussed.
This thesis describes the biological characterization of the mouse XPD gene,
involved in the DNA helix-unwinding step in NER and also in basal transcription
initiation. We generated an XPD knockout mouse and a mouse model for the DNA
repair/basal transcription disorder h·ichothiodystrophy (TTD), which was
accomplished by mimicking a point mutation as found in the XPD gene of a
photosensitive TID patient. The unique spectmm of phenotypes of the TTD mouse
and the molecular defect suspected to underlie it allowed us to investigate
fundamental processes like carcinogenesis, the transcription syndrome and aging in
vivo.
121