Original articleCancer from the outside, aging from the inside: Mouse models to study the consequences of defective nucleotide excision repair
Introduction
Combined biochemical, genetical and cell biological progress in the past decades has culminated in a breakthrough in the insight into the molecular mechanism of nucleotide excision repair (NER). This in turn has provided clues to understanding the molecular basis of the clinical heterogeneity observed in patients with a defect in NER. In recent years, mouse models have been established for the different human NER syndromes. Conventional knockout gene targeting of the mouse XPA gene yielded a model for the prototype DNA repair syndrome xeroderma pigmentosum (XP) with a complete NER defectĀ [1], [2]. Similarly, by targeting the XPC gene, associated with a specific deficiency in the global genome repair (GGR) pathwayĀ [3], [4], a valid model for the group C form of the disease was generated. A mouse model for Cockayne syndrome (CS), with a selective impairment of transcription-coupled repair (TCR) was obtained by mimicking a truncating CSB null allele found in a CS group B patientĀ [5]. Recently, a mutant with a partial repair defect and associated remarkable clinical symptoms of trichothiodystrophy (TTD) was established in the mouse by mimicking a point mutation identified in the XPD gene of a photosensitive TTD patientĀ [6]. Besides mouse mutants with specific NER defects, knockouts and more subtle mutants have been generated for NER proteins that are involved simultaneously in other cellular processes as basal transcription (XPD and XPB)Ā [7] (Weeda, manuscript in preparation), mitotic recombination and cross-link repair (ERCC1)Ā [8], [9] and ubiquitination (mHR23A and B, Ng et al., personal communication). The generation of this series of mouse mutants allows in vivo investigation of some intriguing questions that have puzzled the field, such as the paradoxical absence of cancer development in TTD and CS despite their NER deficiencies, the pathophysiology of the non-NER related clinical symptoms in TTD and CS patients and the proposed involvement of NER and transcription in the process of ageing. This review will focus on data obtained thus far with established NER mouse models and discuss further use of the mouse mutants for unravelling some of the fascinating and medically relevant aspects associated with defects in NER and related processes.
Section snippets
NER deficiency and genotoxic sensitivity
A direct clinical consequence of a deficiency in the NER system is the marked UV (sun) sensitivity and, in XP patients, strong predisposition for tumour development on sun-exposed skinĀ [10]. At the cellular level, UV irradiation induces chemical alterations in the DNA, predominantly cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs). CPDs are repaired in a fast and complete fashion by the TCR machinery in the transcribed strand of active genes but elsewhere in the genome,
XPA and XPC mice
In XP patients, the age of onset of non-melanoma skin tumours is reduced from 60 to 8 years of ageĀ [18]. Similarly, XPA and XPC mice show markedly induced susceptibility to UV-induced skin cancerĀ [1], [2], [3], [4]. At a daily exposure of 80Ā J/m2/d in hairless mouse background, the latency time was reduced by a factor 4.2, from t50 of 320 days in wild-type, to 74 days in XPA mice. A reduction in approximately the same range was seen in XPC mice, suggesting that transcription-coupled repair does
Internal tumours in NER-deficient mice
In addition to UV-induced skin cancer, a defect in NER is anticipated to predispose patients to develop internal tumours because NER lesions are expected to be induced by chemical compounds that enter the body via food, and environmental pollution. Moreover, natural metabolites produced by the cellular metabolism induce NER lesions as well. However, only limited evidence for such a predisposition in XP patients is availableĀ [25].
In light of the above, it is of significance to note that five out
Consequences of multi-functionality of NER proteins
Besides their role in nucleotide excision repair, many individual NER proteins are simultaneously also involved in other cellular processes. As mentioned before, the TCR subpathway accomplishes preferential repair of transcription-blocking lesions from transcribed DNA sequences, involving the CSA and CSB proteins. Recently, direct interaction between the CSB protein and the (elongating) RNApolII complex has been observedĀ [28]. This implies that a CSB defect may affect the process of
Concluding remarks and future perspectives
In recent years, an ever-growing series of NER-deficient mouse mutants has been established. Until now these NER-deficient mice appear valid models for the human syndromes with respect to a number of parameters such as genotoxic sensitivity, the nature of the DNA repair defect, and carcinogenesis. Experimental mouse models provide the opportunity to investigate the role of DNA damage and NER in processes like mutagenesis, apoptosis and immune suppression in vivo, and thus establish the relative
Acknowledgements
We are very grateful to all members of our laboratory and many other colleagues for stimulating discussions and for unpublished results. Our research is supported by the Dutch Cancer Society (project EUR94-763).
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