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43. de Vries, A" vun Ooslrol11, C.T.M., HOtllUis, f.M.A., DOrlanl, P.M., Berg, R . .I.W., de Gruijl, f.R., Wester, P.W., van Kreijl, c.r., Capel, PJ.A., van Steeg, H. and Vt:rbeek, SJ. (J995) Increased susceptibility to ultraviolct-B and carcinogens of mice lacking the DNA excision repair gene XPA, Nature 377, 169-173, 43. Nakane, [[., Takeuchi, S., Yuba, S" SaiJ'o, M., Nakatsu, Y., Ishikawa, T., I [irota, S., Kitamura, Y, Kato, Y., TSlllloda, Y, Miyauchi, II., IIorio, T., Tokunaga, T" Matsunaga, T., Nikaido, 0., Nishi111Ulle, Y., Okada, y, and Tanaka, K. (1995) High incedence of ultraviolet-B- or ehemiealcarcinogen-induced skill tomours in mice lacking the xeroderma pigmentosum group A gene. Nature 377,165-16R. 120 Chapter 6
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
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A MOUSE MODEL FOR TRICHOTHIODYSTROP
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CONTENTS Aim of the thesis 5 Chapte
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AIM OF THE THESIS Nucleotide excisi
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NUCLEOTIDE EXCISION REPAIR AND HUMA
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capacity to generate bulky base add
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strong interaction between XPG and
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XP is characterized by genetic hete
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are diagnosed as a collodion baby (
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23. Gerard, M., Fischer, L., Moncol
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associatcd with mutations in the DN
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CHAPTER 2 MOUSE MODELS TO STUDY THE
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NER DEFICIENCY AND GENOTOXIC SENSIT
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XPC-I-p53+1- mice were more aggress
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tumor development was absent in a g
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[8, 9] reported substantial embryon
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in male sterility. As suggested by
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A point of concern in the extrapola
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CHAPTER 3 DISRUPTION OF THE MOUSE X
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INTRODUCTION To counteract the dele
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RAD3 and RAD25 protein (the latter
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CHAPTER 4 A MOUSE MODEL FOR THE BAS
Page 72 and 73: Death occurs after a short period o
Page 77: Table 3. Comparison of the TTDIBEL
Page 81 and 82: model (UDS, UV survival, pathology,
Page 84 and 85: 33. Stefanini, M., Giliani, S., Nar
Page 88 and 89: INTRODUCTION Genomic instability is
Page 91: correlates very well with literatur
Page 96 and 97: mice, which are histologically noml
Page 98 and 99: proneness in mice cOlTesponds with
Page 101 and 102: 18, Lehmann, A. R., C. F, Arlclt, B
Page 103: CHAPTER 6 SYMPTOMS OF PREMATURE AGI
Page 106 and 107: INTRODUCTION The genome is under co
Page 108 and 109: osteosclerosis, carly depigmentatio
Page 110: oocyte that showed gemlinal vesicle
Page 114 and 115: DISCUSSION Human aging syndromes Ag
Page 116 and 117: lower levels of the anti-oxidants s
Page 118: 6. Nance, M.A and Ben·y, S.A. (199
Page 123 and 124: features are due to an impairment o
Page 125: symptoms in normal aging. Oxidative
Page 130 and 131: In Hoofdstuk 5 worden experimenten
Page 132 and 133: LIST OF PUBLICATIONS Bitter, W., va
Page 134 and 135: DANKWOORD Het schrijven van een dan
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