View PDF Version - RePub - Erasmus Universiteit Rotterdam

More documents

Recommendations

Info

a more detailed overview on the biochemistry of NER, the reader is refelTed to refs. 5 and 6. X-rays Oxygen radicals Alkylating agents Uracil Abasic site 8-0xoguanine Single-strand break BER II DAMAGING AGENT Replication errors A-G Mismatch T -C Mismatch Mismatch Repair II UV-Ught X-rays Polycyclic Aromatic Anti-tumour agents Hydrocarbons (Cis-Pt, MMC) (6-4)PP Bulky adduct CPD NER REPAIR PROCESS II Interstrand Cross-link Double-strand break Recombinational Repair Figure 1 DNA lesions and repair mechanisms. Top: common DNA damaging agents. Middle: examples of lesions that can be introduced by these agents into the DNA double helix. Bottom: the most frequently used repair mechanisms for such lesions. Not depicted but important to realize is that distinct damaging sources can induce similar types of DNA lesions and that also the lesion spectrum of different repair pathways may overlap. Adapted from [6]. Lesions removed by NER NER is the most versatile of all DNA repair mechanisms because it counteracts the deleterious effects of a plethora of structurally unrelated DNA lesions. The majority of the numerous chemicals to which NER-deficient cells are sensitive share the 10 Chapter I
capacity to generate bulky base adducts which can cause significant distortion of the DNA helix [7]. The clinically most relevant NER substrates are cis-syn-cyclobutane dimers (CPDs) and pyrimidine (6-4) pyrimidone photoproducts (6-4PPs). Both are fonned between adjacent pyrimidines, and they constitute the two major classes of lesions induced by solar UV light. The more helix-distorting 6-4PPs are repaired 5-fold faster than CPDs and, although CPDs are more abundant, UV hypersensitivity of rodent and human cell lines correlates better with the capacity to excise 6-4PPs than with CPD removal from the genome [8]. Other NER substrates include bulky chemical adducts such as large polycyclic aromatic hydrocarbons (induced by compounds in cigarette smoke) and the particularly distorting interstrand crosslinks, induced by cisplatin and probably also by certain cellular metabolites [9]. NER has also been implicated in removal of small base damages induced by alkylating and oxidizing agents which are generally not helix distortive [7]. Base excision repair is considered as the main pathway involved in repair of these types of damage, but NER may be considered as a back-up system [10,11]. The relative importance of NER in repair of alkyl and oxidative damage has not been fitmly established yet. However, its involvement emphasizes the versatility of the NER mechanism, which also explains how various endogenous and exogenous genotoxic agents may contribute to the large spectrum of clinical symptoms associated with defects in one of the NER components. The NER mechanism The NER process involves the action of about 20-30 proteins in successive 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 filled by DNA repair synthesis, followed by strand ligation. An in part speculative model for NER is presented below and in Figure 2. Damage recognition Binding of the XPC/hHR23B complex is considered as the initial, damagerecognizing step in NER [12], recruiting the repair protein machinery to the damaged site. Since locally premelted DNA is also sufficient the NER machinery to act in the absence of XPC/hHR23B [13], the complex may slightly increase singlestrandedness at the site of the lesion. A role for the XPE protein in damage recognition has been proposed, because it has affinity for damaged DNA [14]. Also XPA displays a high affinity for damaged DNA [15], especially in a single stranded context. Nucleotide excision repair and human syndromes 11
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: NUCLEOTIDE EXCISION REPAIR AND HUMA
Page 14 and 15: strong interaction between XPG and
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
Page 63:
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 121 and 122:
SUMMARY AND CONCLUSIONS DNA damage
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
show all

View PDF Version - RePub - Erasmus Universiteit Rotterdam

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?