A Mouse Model for Trichothiodystrophy

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