XP VARIANT--A HUMAN MUTATOR GENE FOR UV DAMAGE

环境致癌物和遗传毒性物质对人类健康的危害 被一系列特定的基因家族和多态性修饰。 对这些基因的理解是通过遗传疾病来实现的 对环境因素的敏感性增加，特别是 紫外线，其中DNA修复机制发挥了关键作用。 作用 着色性干皮病和相关疾病，如Cockayne 综合征和甲状腺营养不良已经提供了关于 DNA损伤和切除修复在癌发生中作用， 揭示了修复和基因转录之间的基本联系 这可能解释了涉及神经系统和 发育障碍 不太清楚的是， 受损的DNA被几种人类疾病忠实地复制 代表复制保真度和细胞周期控制的缺陷。 这些疾病增加了对癌症的易感性， 染色体和遗传不稳定性包括共济失调毛细血管扩张症，布卢姆 综合征、发育不良痣综合征和XP变体。 XP变体 是特别感兴趣的，因为光化的临床症状 致癌作用和偶尔出现的神经功能衰退， 与切除缺陷XP组A至G无法区分，但 细胞显示正常切除收割机。 因此，XP变体代表 DNA损伤过程与DNA保真度之间的联系 复制和修复，而其他XP组代表减少 在修复的定量方面。 我们提出一项研究， 克隆XP变体和相关基因，并了解其 生物化学 我们已经检测到染色体不稳定性增加 这对于SV 40转化的XP变体来说是独特的，这表明， XPV基因产物位于T抗原依赖性途径上。初步 证据已经为我们提供了新的见解， XPV表型，甲基转移的生化途径， 遗传不稳定性;我们克隆了一个基因参与表达 变异细胞中SCES增加，与同型半胱氨酸同源 它位于1号染色体上，在2号染色体上的3 ′ UTR有改变， XPV细胞系，并提出了识别其他基因的策略 参与XPV表型。

Human health risks from environmental carcinogens and genotoxic agents are modified by a range of specific gene families and polymorphisms. Progress in understanding these genes has come through genetic diseases that show increased susceptibility to environmental agents, especially ultraviolet light, and in which DNA repair mechanisms play a pivotal role. Xeroderma pigmentosum and related diseases such as Cockayne syndrome and trichothiodystrophy have been extremely informative about the role of DNA damage and excision repair in carcinogenesis, and have revealed a fundamental linkage between repair and gene transcription which may explain varied clinical symptoms involving neurological and developmental disorders. Less well understood are mechanisms by which damaged DNA is faithfully replicated by several human diseases appear to represent defects in replication fidelity and cell cycle control. These diseases which show increases susceptibility to cancer and chromosomal and genetic instability include ataxia telangiectasia, Bloom syndrome, dysplastic nevus syndrome and the XP variant. The XP variant is of especial interest because the clinical symptoms of actinic carcinogenesis and occasional cases of neurological decline are indistinguishable from excision defective XP groups A through G, yet cells show normal excision reaper. The XP variant therefore represents a linkage between the processing of DNA damage and the fidelity of DNA replication and repair whereas the other XP groups represent reductions in quantitative aspects of repair. We propose a study that will lead to cloning the XP variant and related genes and understanding its biochemistry. We have already detected increased chromosome instability that is distinctive for SV40 transformed XP variants, suggesting that the XPV gene product lies on T antigen-dependent pathways. Preliminary evidence has already provided us new insights into relationship between the XPV phenotype, the biochemical pathways of methyl transfer and genetic instability; we have cloned one gene involved in expression of increased SCES in variant cells, which is homologous to a homocysteine hydrolase and is on chromosome 1 and has alterations in its 3'utr in 2 XPV cell lines, and present strategies for identifying additional genes involved in the XPV phenotype.