Tissue specific mutagenic and carcinogenic responses in NER defective mouse models

Abstract

Several mouse models with defects in genes encoding components of the nucleotide excision repair (NER) pathway have been developed. In NER two different sub-pathways are known, i.e. transcription-coupled repair (TC-NER) and global-genome repair (GG-NER). A defect in one particular NER protein can lead to a (partial) defect in GG-NER, TC-NER or both. GG-NER defects in mice predispose to cancer, both spontaneous as well as UV-induced. As such these models (Xpa, Xpc and Xpe) recapitulate the human xeroderma pigmentosum (XP) syndrome. Defects in TC-NER in humans are associated with Cockayne syndrome (CS), a disease not linked to tumor development. Mice with TC-NER defects (Csa and Csb) areexcept for the skin -not susceptible to develop (carcinogen-induced) tumors. Some NER factors, i.e. XPB, XPD, XPF, XPG and ERCC1 have functions outside NER, like transcription initiation and inter-strand crosslink repair. Deficiencies in these processes in mice lead to very severe phenotypes, like trichothiodystrophy (TTD) or a combination of XP and CS. In most cases these animals have a (very) short life span, display segmental progeria, but do not develop tumors. Here we will overview the available NER-related mouse models and will discuss their phenotypes in terms of (chemical-induced) tissue-specific tumor development, mutagenesis and premature aging features.

The role of DNA exonucleases in protecting genome stability and their impact on ageing

“…These phenotypes are thought to arise through loss of XPG's role in stabilising transcription, rather than its activity in DNA repair (Friedberg and Wood 2007). Hence XPG mutation can give rise to various symptoms of both CS and XP including premature ageing (Friedberg and Wood 2007;Wijnhoven et al 2007). In addition to its incision activity (O'Donovan et al 1994;Habraken et al 1994b), XPG belongs to the FEN1/RAD2 family because of its conserved 5′-3′ exonuclease activity (Habraken et al 1994a, see Table 2).…”

Transcription-coupled repair and apoptosis provide specific protection against transcription-associated mutagenesis by ultraviolet light

“…17 These patients are proficient for the global genome NER that might remove a fraction of the mutagenic CPD lesions from transcribed templates in the absence of TCR, thereby suppressing carcinogenesis, as was recently found for CSB-deficient mice. 18 Nevertheless, the remarkable lack of skin cancer supports the idea that the efficient induction of apoptosis by arrested transcription complexes, despite the presence of TAP, provides protection against oncogenic transformation of the cell.…”

Dysmyelination not demyelination causes neurological symptoms in preweaned mice in a murine model of Cockayne syndrome

“…In our studies, we compared strains homozygous and heterozygous for Csb, on the Xpc-negative background, to identify those features of the pathology dictated by complete loss of Csb functions. The Xp-c strain exhibits no reported neurological dysfunction but, like XP-C patients, develops skin cancer after exposure to UV light (30). The mild phenotype of the Csb m/m strain alone and the very severe phenotype of the double mutant are reminiscent of the human extremes of CS symptoms that present as the UV s and the COFS disorders.…”