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strong interaction between XPG and TFIIH [34] suggests that TFIIH is involved in XPG positioning. Gap-filling and ligation The last step in the NER reaction, gap-filling of the excised patch, is used for assaying NER activity ill vitro and ill vivo (unscheduled DNA synthesis, DDS). An in vitro reconstituted repair reaction showed that efficient repair synthesis occurs after addition of the mammalian DNA replication factors RPA, RF-C, PCNA, and DNA polymerase I) and 8 [35]. The NER reaction is completed by ligation of the newly synthesized DNA. DNA ligase I is a likely candidate for this reaction, because mutations in the corresponding gene can give rise to an UV -sensitive phenotype [36]. Two different pathways The reaction mechanism described above is designated global genome repair (GGR), which removes DNA damage from the whole genome. In contrast, lesions in the transcribed strand of actively transcribed genes are preferentially repaired via the NER-subpathway transcription-coupled repair (TCR) [37]. Both processes are essentially the same except for the initial damage recognition step, which is perfOlmed by XPClhHR23b in GGR. This is the only NER factor dispensable for TCR [38] (see Figure 2a). Instead, the stalled RNA polymerase II complex itself seems to be the damage recognition signal in TCR and attracts the NER machinery [13]. Because a stalled RNA polymerase II sterically hinders accessibility of NER proteins, it has to withdraw or dissociate from the lesion for repair to occur [39]. Cells with a defect in the CSA or CSB genes are specifically defective in TCR; the CSA protein contains WD-repeats involved in fonnation of multi protein complexes [40] and CSB is a member of the SWIISNF family of DNA-dependent ATPases implicated in chromatin remodeling [41]. An interaction between CSB and RNA polymerase II was found [42], suggesting that CSA and CSB are involved in processing of a stalled RNA polymerase complex. However, the precise role of CSA and CSB in the process ofTCR remains unclear [43]. 14 Chapter 1
NUCLEOTIDE EXCISION REPAIR DEFICIENCY SYNDROMES The consequences of a defect in one of the NER proteins are apparent from three rare recessive syndromes: xerodenna pigmentosum, Cockayne syndrome, and the photosensitive fmm of the brittle hair disorder trichothiodystrophy. Seven complementation groups have been identified in XP (XP-A to XP-G), two in CS (CS-A and CS-B) and three in TID (XP-B, XP-D, and TID-A). Sun-sensitive skin is associated with skin cancer predisposition in the case of XP, but not in CS and TTD. In addition, the spectrnm of clinical symptoms differs considerably between the three syndromes (summarised in Table I) and many of the abnormalities of CS and TID are difficult to comprehend as a consequence of defective NER. Xeroderma pigmentosum Parchment skin (xeroderma) and freckles (pigmentosum) are cutaneous abnormalities of XP patients, which are strikingly limited to sun-exposed areas of the skin, and sun exposure of XP patients generally results in progressive degenerative alterations of the skin and eyes [44]. The mean age of onset of these symptoms is 2 years [45]. Furthermore, XP is associated with a thousand-fold increased risk to develop skin cancers, which are also largely confined to sunexposed areas like the face, neck, head, and even the tip of the tongue. XP patients mainly develop basal cell carcinomas and squamous cell carcinomas, and less frequently melanomas. The mean age of onset of first skin neoplasm is 8 year, which is nearly 50 years earlier compared to the general population [45]. Many XP patients die of neoplasia, reducing the lifespan by approximately 30 years. Moreover, XP patients have a ten- to twenty-fold increased risk of developing internal cancers under the age of 20 years [46]. Considering the involvement of NER in repair of certain chemically induced DNA lesions, as well as in repair of lesions induced by cellular metabolites, either category of lesions may playa role in these internal neoplasms. A fraction of XP patients (-18%) displays progressive neurologic abnormalities. The underlying condition seems to be primary neuronal degeneration with loss of neurons. At the severe end of the clinical spectrum are patients with DeSanctis Cacchione syndrome with microcephaly, progressive mental deterioration, dwarfism and impaired sexual development [47]. It appears that individuals who only have a partial NER defect, like XP-F and XP-C patients, tend to develop neurologic symptoms not at all or later in life compared to patients with more severe NER defects (e.g. XP-A) [44]. A possible explanation for the onset of neurological abnormalities in XP patients is that defective repair in nerve cells of endogenous (oxidative) NER lesions induces neuronal death [48]. Nucleotide excision repair and human syndromes 15
Page 1 and 2: A MOUSE MODEL FOR TRICHOTHIODYSTROP
Page 3 and 4: CONTENTS Aim of the thesis 5 Chapte
Page 5: AIM OF THE THESIS Nucleotide excisi
Page 9 and 10: NUCLEOTIDE EXCISION REPAIR AND HUMA
Page 11 and 12: capacity to generate bulky base add
Page 16 and 17: XP is characterized by genetic hete
Page 18: are diagnosed as a collodion baby (
Page 22 and 23: 23. Gerard, M., Fischer, L., Moncol
Page 24 and 25: associatcd with mutations in the DN
Page 27: CHAPTER 2 MOUSE MODELS TO STUDY THE
Page 30: NER DEFICIENCY AND GENOTOXIC SENSIT
Page 34 and 35: XPC-I-p53+1- mice were more aggress
Page 36 and 37: tumor development was absent in a g
Page 38 and 39: [8, 9] reported substantial embryon
Page 41 and 42: in male sterility. As suggested by
Page 43: A point of concern in the extrapola
Page 47: CHAPTER 3 DISRUPTION OF THE MOUSE X
Page 50: INTRODUCTION To counteract the dele
Page 57: RAD3 and RAD25 protein (the latter
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CHAPTER 4 A MOUSE MODEL FOR THE BAS
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Death occurs after a short period o
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Table 3. Comparison of the TTDIBEL
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model (UDS, UV survival, pathology,
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33. Stefanini, M., Giliani, S., Nar
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INTRODUCTION Genomic instability is
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correlates very well with literatur
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mice, which are histologically noml
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proneness in mice cOlTesponds with
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18, Lehmann, A. R., C. F, Arlclt, B
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CHAPTER 6 SYMPTOMS OF PREMATURE AGI
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INTRODUCTION The genome is under co
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osteosclerosis, carly depigmentatio
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oocyte that showed gemlinal vesicle
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DISCUSSION Human aging syndromes Ag
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lower levels of the anti-oxidants s
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6. Nance, M.A and Ben·y, S.A. (199
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SUMMARY AND CONCLUSIONS DNA damage
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features are due to an impairment o
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symptoms in normal aging. Oxidative
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In Hoofdstuk 5 worden experimenten
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LIST OF PUBLICATIONS Bitter, W., va
Page 134 and 135:
DANKWOORD Het schrijven van een dan
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