View PDF Version - RePub - Erasmus Universiteit Rotterdam
View PDF Version - RePub - Erasmus Universiteit Rotterdam
View PDF Version - RePub - Erasmus Universiteit Rotterdam
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AIM OF THE THESIS<br />
Nucleotide excision repair (NER) is a versatile DNA repair mechanism that<br />
safeguards the genome from many types of DNA damages. The importance ofNER<br />
is highlighted by three inherited human disorders with defective NER: xeroderma<br />
pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy (TTD). XP<br />
patients display enhanced susceptibility to sunlight-induced skin cancer, but CS and<br />
TTD are not associated with increased cancer susceptibility despite an NER defect.<br />
Moreover, CS and TID patients are characterized by a broad range of<br />
neurodevelopmental abnormalities, which al:e difficult to rationalise as a<br />
consequence of a defect in NER. One of the NER genes, XPD, is implicated in XP,<br />
XP with combined features of CS, and TTD. XPD is a subunit of the dually<br />
functional transcription factor IIH (TFIIH) complex, involved in NER and basal<br />
transcription initiation. It was hypothesized that mutations in XPD may not only<br />
affect NER, causing XP and photosensitivity in TID, but may also impair the<br />
tTanscription function of TFIIH accounting for the neurodevelopmental<br />
abnormalities in CS and TID. The aim of the work outlined in this thesis is to gain<br />
insight into the molecular basis of the clinical symptoms associated with defects in<br />
the XPD gene, and into the enigmatic difference in cancer predisposition between<br />
XP and TTD patients. To accomplish this, we aimed at generating mouse models<br />
for XP, CS and TID. Therefore, disease-specific mutations identified in the XPD<br />
gene of XP, XP/CS and photosensitive TID patients were mimicked in the mouse<br />
XPD gene via homologous recombination in embryonic stem cells. Chapter 1 of<br />
this thesis reviews the NER mechanism and the clinical symptoms associated with<br />
XP, CS and TID. In chapter 2, literature on NER-deficient mouse models is<br />
reviewed and the phenotypical consequence of the role of NER proteins in DNA<br />
repair, mitotic recombination and transcription is discussed. Chapter 3 and 4<br />
describe the generation and characterization ofaXPD knockout and TID mouse<br />
model respectively. Further analysis of the TID mouse model revealed cancer<br />
predisposition and signs of premature aging as described in Chapter 5 and 6.