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: 6178559
• 负责人: JAMES E CLEAVER
• 金额: $ 18.56万
• 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 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6178559
• 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性物质对人类健康的危害