XP VARIANT--A HUMAN MUTATOR GENE FOR UV DAMAGE

XP 变体——紫外线损伤的人类突变基因

• 批准号: 2018664
• 负责人: JAMES E CLEAVER
• 金额: $ 18.17万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-02-01 至 1998-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2018664
• 关键词: DNA damage; DNA repair; animal genetic material tag; complementary DNA; gene complementation; genetically modified animals; laboratory mouse; neoplasm /cancer genetics; nucleic acid sequence; radiation carcinogenesis; tumor suppressor genes; ultraviolet radiation; xeroderma pigmentosum

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.

环境致癌物和基因毒剂对人类健康造成的风险 被一系列特定基因家族和多态性修饰。 通过遗传疾病了解这些基因取得了进展 显示出对环境因素的敏感性增加，特别是 紫外线，其中 DNA 修复机制发挥着关键作用 角色。 着色性干皮病和相关疾病，例如 Cockayne 综合征和毛发硫营养不良症的信息非常丰富 DNA 损伤和切除修复在致癌过程中的作用 揭示了修复和基因转录之间的基本联系 这可以解释涉及神经系统和疾病的各种临床症状 发育障碍。 不太为人所知的是其机制 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。 这些疾病显示出对癌症的易感性增加 染色体和遗传不稳定包括共济失调性毛细血管扩张症、Bloom 综合征、发育不良痣综合征和 XP 变异。 XP 变体 特别令人感兴趣，因为光化性的临床症状 致癌作用和偶发的神经功能衰退病例 与 A 至 G 组切除缺陷 XP 无法区分，但 细胞显示正常切除收割者。 XP 变体因此代表 DNA 损伤处理与 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，该研究将导致 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 这是 SV40 转化的 XP 变体的独特之处，表明 XPV 基因产物依赖于 T 抗原依赖性途径。初步的 证据已经为我们提供了关于两者之间关系的新见解 XPV 表型、甲基转移的生化途径和 遗传不稳定性；我们克隆了一个参与表达的基因 变异细胞中的 SCES 增加，与同型半胱氨酸同源 水解酶，位于 1 号染色体上，2 号染色体的 3'utr 发生改变 XPV 细胞系，并提出识别其他基因的策略 参与 XPV 表型。