Disease relevance of Xpa

• To examine whether these p53 patches can be used as tumour risk indicators, we made an extensive comparison of the induction kinetics of these patches and carcinomas in genetically modified mice with various defects in nucleotide excision repair (NER), i.e. xeroderma pigmentosum A (Xpa), Xpc and Cockayne syndrome B (Csb) and wild-type mice [1].
• Subsequently Xpa and Xpc knockouts have proved to be good models for the human NER deficiency disease, xeroderma pigmentosum, leading to speculation that the recombination, rather than the NER deficit is the key to the Ercc1 knockout phenotype [2].
• These features were not seen in nucleotide excision repair-deficient Xpa-/- mice, but are characteristic of Fanconi anemia, a human cancer syndrome caused by defects in interstrand crosslink repair [3].
• On UVB treatment (250 J/m(2)), Xpa(-/-) and Csb(-/-) mice revealed an extensive apoptotic response in the skin, a blockage of cell cycle progression of epidermal cells, and strong hyperplasia [4].
• Despite raising >1,600 nevi, only six melanomas arose in our experiments with Ink4a/Arf knockout mice (five of which in Xpa(+/+) mice at high UV dosages) [5].

High impact information on Xpa

• We investigated the impact of deficiencies in NER subpathways on apoptosis, hyperplasia, and cell cycle progression in the epidermis of UVB-exposed CS group B (Csb(-/-)) mice (no TCR), XP group C (Xpc(-/-)) mice (no GGR), and XP group A (Xpa(-/-)) mice (no TCR and no GGR) [4].
• Therefore, hypermutation was studied in mice deficient for either the DNA nucleotide excision repair gene Xpa or the mismatch repair gene Pms2 [6].
• The Xpa(-/-) mice proved exquisitely sensitive to UV-driven nevus induction, indicating the involvement of pyrimidine dimer DNA lesions, but Xpa(+/+) mice developed many more nevi (>40 per mouse) at high UV dosages not tolerated by Xpa(-/-) mice [5].
• p53 heterozygosity results in an increased 2-acetylaminofluorene-induced urinary bladder but not liver tumor response in DNA repair-deficient Xpa mice [7].
• Short-term assays revealed a decreased apoptotic response in Xpa/p53(+/-) mice, pointing in vivo toward a link between NER and p53-mediated apoptosis [7].

Biological context of Xpa

• Xpa mice completely lack the nucleotide excision repair pathway, and as such they are sensitive to some classes of genotoxic compounds [8].
• It is concluded that while increased genomic instability could play a causal role in the mildly accelerated aging phenotype in the Xpa-null mice or in the severe progeroid symptoms of the Ercc1-mutant mice, shortened lifespan in mice with defects in transcription-related repair do not depend upon increased mutation accumulation [9].
• Repair-defective Xpa-/- mice were 7-10-fold more sensitive to sunburn cell induction than wild-type mice, indicating that 86-90% of the ultraviolet B signal for keratinocyte apoptosis involved repairable photoproducts in DNA; the remainder involves unrepaired DNA lesions or nongenomic targets [10].
• Homozygous inactivation of Xpa, Csb, or Xpc nucleotide excision repair genes directed the accumulation of DNA photoproducts to specific genome regions [10].
• Interestingly, however, mice completely deficient in both NER and p53 (Xpa/p53(-/-) mice) showed a dramatic increase of hepatocellular proliferation accompanied by lacZ reporter gene mutations [7].

Anatomical context of Xpa

• DMBA-induced SCE frequencies in mouse dermal fibroblasts were significantly enhanced in Xpa- and Csb-, but not in Xpc-deficient background compared to the frequency in normal fibroblasts [11].
• In a previous study, we found UVB-induced accumulation of tetraploid (4N) keratinocytes in the epidermis of Xpc(-/-) mice (no GGR), but not in Xpa(-/-) (no TCR and no GGR) or in wild-type (WT) mice [12].
• The incidence of tumors was higher in the Xpa/p53 mice at 1500 ppb, mainly attributable to 5 osteosarcomas in males and 2 in females, but also 4 pituitary adenomas, testicular interstitial cell adenomas in 4 males, and single incidences of cerebral glioma, phaeochromocytoma, and cervical fibrosarcoma [13].
• Astrocytes from the cerebellum of wild type, Aag(-/-) or Xpa(-/-) mice were essentially insensitive to CAA at the concentrations tested [14].
• Correspondingly, DNA repair-deficient xeroderma pigmentosum A (Xpa) mice proved exquisitely sensitive to melanocyte proliferation induction by UVB exposure [15].

Associations of Xpa with chemical compounds

• Phenacetin acts as a weak genotoxic compound preferentially in the kidney of DNA repair deficient Xpa mice [8].
• Suppression of UV carcinogenesis by difluoromethylornithine in nucleotide excision repair-deficient Xpa knockout mice [16].
• Assessment of carcinogenicity of di(2-ethylhexyl)phthalate in a short-term assay using Xpa-/- and Xpa-/-/p53+/- mice [17].
• The potential of Xpa-/- and Xpa-/-/p53+/- mice for short-term carcinogenicity assays was evaluated with di(2-ethylhexyl)phthalate (DEHP) [17].
• Neuronal and astrocyte cell cultures prepared from the cerebellum of wild type (C57BL/6) mice or Aag(-/-) or Xpa(-/-) mice were treated with 0.1-50 microM CAA for 24h to 7 days and examined for cell viability, DNA fragmentation (TUNEL labeling), nuclear changes, and glutathione levels [14].

Other interactions of Xpa

• Phenacetin exposure induced a significant increase of lacZ mutations in the kidney of both Xpa and Xpa/p53 mice [8].
• Here we show that this mutation is not a hot spot in Xpa or Csa mutant mice [18].
• Hprt mutant frequencies in Xpa-/- and Csb-/- mice that both have a defect in this NER subpathway, remained low during ageing [19].
• In this study, we investigated the impact of loss of XPA function on PhIP-induced intestinal tumorigenesis in F1 offspring of Min/+ (Apc(+/-)) mice crossed with Xpa gene-deficient mice [20].
• Severe growth retardation and short life span of double-mutant mice lacking Xpa and exon 15 of Xpg [21].

Analytical, diagnostic and therapeutic context of Xpa

• Surprisingly, while all intraperitoneally-treated Xpc(-/-) mice survived a dose of 40 mg/kg DMBA, a substantial fraction of the treated Xpa(-/-) and Csb(-/-) mice died a few days after treatment with a 20-fold lower dose [11].
• The DFMO treatment reduced the tumor load but did not offer the Xpa knockout mice full protection against UV carcinogenesis [16].
• All compounds identified thus far are true (human) carcinogens, and, therefore, the authors believe that the Xpa/p53+/- mouse model is an excellent candidate for a future replacement of the chronic mouse bioassay, at least for certain classes of chemicals [22].

References