Disease relevance of Ercc6

• Mutations in the CSB gene cause Cockayne syndrome (CS), a DNA repair disorder characterized by UV sensitivity and severe physical and neurological impairment [1].
• CSB(-/-) mice are sensitive to UV-induced skin cancer but show no increased rate of spontaneous cancer [2].
• The median latency time of squamous cell carcinomas (diameters > or = 1 mm) is 84 days for the XPC -/- mice, 115 days for the CSB -/- mice, and 234-238 days for the heterozygous and wild-type control groups [3].
• In addition, CSB -/- mice develop marked parakeratosis, whereas XPC -/- mice and controls do not [3].
• To determine to what extent a TCR deficiency affects carcinogen-induced mutagenesis and carcinogenesis, CS group B correcting gene (CSB)-deficient mice were treated with the genotoxic carcinogen benzo(a)pyrene (B[a]P) at an oral dose of 13 mg/kg body weight, three times a week [4].

High impact information on Ercc6

• Mice with a targeted deletion of the CSB gene (Csb(-/-)) exhibit a much milder ataxic phenotype than human patients [5].
• Here we show that mice lacking both the XPA (XP-group A) and CSB (CS-group B) genes in contrast to the single mutants display severe growth retardation, ataxia, and motor dysfunction during early postnatal development [6].
• CSB functions in the transcription-coupled repair subpathway of nucleotide excision repair [1].
• CSB(-/-) Ink4a/ARF(-/-) MEFs were also more sensitive to UV-induced p53 induction and UV-induced apoptosis than were Ink4a/ARF(-/-) MEFs [2].
• Moreover, CSB(-/-) Ink4a/ARF(-/-) mouse embryo fibroblasts (MEFs) exhibited a lower colony formation rate after low-density seeding, a lower rate of H-Ras-induced transformation, slower proliferation, and a lower mRNA synthesis rate than Ink4a/ARF(-/-) MEFs [2].

Biological context of Ercc6

• The CSB(-/-) p53(-/-) MEFs demonstrated lower colony formation efficiency, a lower proliferation rate, a lower mRNA synthesis rate, and a higher rate of UV-induced cell death than p53(-/-) MEFs [2].
• The Cockayne syndrome B (CSB) gene product is involved in the repair of various types of base modifications in actively transcribed DNA sequences [7].
• CSB mice, defective in transcription-coupled repair, were far more sensitive for immunosuppression as were XPA mice, defective in both transcription-coupled repair and global genome repair [8].
• Lymph node cell numbers were increased very significantly in XPA, mildly increased in CSB, and not in XPC mice [9].

Anatomical context of Ercc6

• B[a]P treatment gave rise to increased mutant frequencies at lacZ in all of the organs tested without a significant difference between CSB-/- and wild-type mice, whereas B[a]P-induced Hprt mutant frequencies in splenic T-lymphocytes were significantly more enhanced in CSB-/- mice than in control mice [4].

Associations of Ercc6 with chemical compounds

• The sequence data obtained from Hprt mutants indicate that B[a]P adducts at guanine residues were preferentially removed from the transcribed strand of the Hprt gene in control mice but not in CSB-/- mice [4].
• Therefore, it may be either chondroitin sulfate B (CSB) (dermatan sulfate) or one of the 'chondroitin sulfate isomers' (D-H) [10].

Other interactions of Ercc6

• Collectively, these results indicate that the antineoplastic effect of CSB gene disruption is at least partially p53 independent; it may result from impaired transcription or from apoptosis secondary to environmental or endogenous DNA damage [2].

References