The incidence of cutaneous melanoma is rising rapidly in a number of countries. The key environmental risk factor is exposure to the ultraviolet (UV) component in sunlight. The nucleotide excision repair (NER) pathway deals with the main forms of UV-induced DNA damage. We have investigated the hypothesis that polymorphisms in NER genes constitute genetic susceptibility factors for melanoma. However, not all melanomas arise on sun-exposed sites and so we investigated the hypothesis that genes involved in other pathways for the repair of oxidative DNA damage may also be involved in susceptibility to melanoma. Scotland, with its high incidence of melanoma and stable homogeneous population, was ideal for this case-control study, involving 596 Scottish melanoma patients and 441 population-based controls. Significant associations were found for the NER genes ERCC1 and XPF, with the strongest associations for melanoma cases aged 50 and under [ERCC1 odds ratio (OR) 1.59, P = 0.008; XPF OR 1.69, P = 0.003]. Although an XPD haplotype was associated with melanoma, it did not contain the variant 751 Gln allele, which has been associated with melanoma in some previous studies. No associations were found for the base excision repair and DNA damage response genes investigated. An association was also found for a polymorphism in the promoter of the vitamin D receptor gene, VDR (OR 1.88, P = 0.005). The products of the two NER genes, ERCC1 and XPF, where associations with melanoma were found, act together in a rate-limiting step in the repair pathway.
BackgroundInfertility affects ∼20% of couples in Europe and in 50% of cases the problem lies with the male partner. The impact of damaged DNA originating in the male germ line on infertility is poorly understood but may increase miscarriage. Mouse models allow us to investigate how deficiencies in DNA repair/damage response pathways impact on formation and function of male germ cells. We have investigated mice with deletions of ERCC1 (excision repair cross-complementing gene 1), MSH2 (MutS homolog 2, involved in mismatch repair pathway), and p53 (tumour suppressor gene implicated in elimination of germ cells with DNA damage).Principal FindingsWe demonstrate for the first time that depletion of ERCC1 or p53 from germ cells results in an increased incidence of unrepaired DNA breaks in pachytene spermatocytes and increased numbers of caspase-3 positive (apoptotic) germ cells. Sertoli cell-only tubules were detected in testes from mice lacking expression of ERCC1 or MSH2 but not p53. The number of sperm recovered from epididymes was significantly reduced in mice lacking testicular ERCC1 and 40% of sperm contained DNA breaks whereas the numbers of sperm were not different to controls in adult Msh2 −/− or p53 −/− mice nor did they have significantly compromised DNA.ConclusionsThese data have demonstrated that deletion of Ercc1, Msh2 and p53 can have differential but overlapping affects on germ cell function and sperm production. These findings increase our understanding of the ways in which gene mutations can have an impact on male fertility.
Apolipoprotein E (APOE)-ɛ4 is associated with a deleterious outcome after ischemic brain injury, which may involve abnormal regulation of mitochondrial function. We have assessed the mitochondrial proteomic response of APOE-ɛ3 and APOE-ɛ4 transgenic mice to transient global ischemic injury in the hippocampus. A genotype-dependent increase in ApoE levels in mitochondria was observed after ischemia, with APOE-ɛ4 mice showing significantly greater increases than APOE-ɛ3 mice. Quantitative analysis of the mitochondria-enriched fractions was performed using liquid-chromatography mass spectrometry coupled to label-free analysis. Of the 1,067 identified proteins, 274 were mitochondria associated. Mitochondrial protein expression was significantly different between genotypes under basal conditions as well as in response to global ischemia. A total of 12 mitochondrial proteins (including respiratory chain proteins NDUFA11, NDUFS3, NDUF5B, ATP5J, as well as ETFA, CYB5B, ATP6V1A, HSPA1B, OXR1, GLUL, IARS2, and PHYHIPL) were significantly altered with respect to genotype, global ischemia, or their interaction (P<0.01). A compelling interactome, created using proteins found to be significantly modulated by global ischemia (P<0.05), involved proteins that regulate energy production and oxidative stress. Thus, APOE genotype has a differential effect on the mitochondrial protein expression in the absence and presence of an injury, which may underlie the differing genotype susceptibility.
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