XP VARIANT--A HUMAN MUTATOR GENE FOR UV DAMAGE

XP 变体——紫外线损伤的人类突变基因

基本信息

项目摘要

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.
环境致癌物质和遗传毒性物质对人类健康的风险 被一系列特定的基因家族和多态所改变。 了解这些基因的进展是通过遗传病取得的。 这表明对环境因素的敏感性增加,特别是 紫外线,其中DNA修复机制起着关键作用 角色。色素性干皮病与Cockayne等相关疾病 综合征和毛发硫营养不良症提供了非常丰富的信息 DNA损伤和切除修复在癌症发生中的作用 揭示了修复和基因转录之间的基本联系 这可能解释了各种临床症状,包括神经系统和 发育障碍。鲜为人知的是, 受损的DNA被几种人类疾病忠实地复制出来 代表复制保真度和细胞周期控制方面的缺陷。 这些疾病表现出增加癌症易感性和 染色体和遗传不稳定包括共济失调毛细血管扩张,Bloom 综合征、发育不良痣综合征和XP变种。XP变种 尤其令人感兴趣,因为光化症的临床症状 癌症的发生和偶尔出现的神经功能衰退的病例是 无法与切除有缺陷的XP组A到G区分,但 细胞显示正常的割除细胞。因此,XP变体代表 DNA损伤的处理与DNA的保真度之间的联系 复制和修复,而其他XP组代表减少 在修缮的数量方面。我们建议进行一项研究,这项研究将导致 克隆XP变异体及其相关基因并了解其 生物化学。我们已经检测到染色体不稳定性增加 这对于SV40转换的XP变体来说是独一无二的,这表明 XPV基因产物位于T抗原依赖的途径上。初步 证据已经为我们提供了关于 XPV的表型,甲基转移的生化途径和 遗传不稳定性;我们已经克隆了一个参与表达的基因 变异细胞中SCE增加,与同型半胱氨酸同源 该基因位于1号染色体上,其3‘非编码区在2号染色体上发生了改变。 XPV细胞系,并提出了识别其他基因的策略 参与了XPV的表型。

项目成果

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JAMES E CLEAVER其他文献

JAMES E CLEAVER的其他文献

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{{ truncateString('JAMES E CLEAVER', 18)}}的其他基金

DNA Damage and Neurodegeneration in Cockayne Syndrome
科凯恩综合征中的 DNA 损伤和神经变性
  • 批准号:
    7439076
  • 财政年份:
    2006
  • 资助金额:
    $ 18.51万
  • 项目类别:
DNA Damage and Neurodegeneration in Cockayne Syndrome
科凯恩综合征中的 DNA 损伤和神经变性
  • 批准号:
    7252003
  • 财政年份:
    2006
  • 资助金额:
    $ 18.51万
  • 项目类别:
DNA Damage and Neurodegeneration in Cockayne Syndrome
科凯恩综合征中的 DNA 损伤和神经变性
  • 批准号:
    7587300
  • 财政年份:
    2006
  • 资助金额:
    $ 18.51万
  • 项目类别:
DNA Damage and Neurodegeneration in Cockayne Syndrome
科凯恩综合征中的 DNA 损伤和神经变性
  • 批准号:
    7141167
  • 财政年份:
    2006
  • 资助金额:
    $ 18.51万
  • 项目类别:
Cutaneous oncology program
皮肤肿瘤学项目
  • 批准号:
    6211795
  • 财政年份:
    1999
  • 资助金额:
    $ 18.51万
  • 项目类别:
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
  • 财政年份:
    1998
  • 资助金额:
    $ 18.51万
  • 项目类别:
The XP Variant: A Human Mutator Gene for UV Damage
XP 变体:导致紫外线损伤的人类突变基因
  • 批准号:
    6908109
  • 财政年份:
    1998
  • 资助金额:
    $ 18.51万
  • 项目类别:
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
  • 财政年份:
    1998
  • 资助金额:
    $ 18.51万
  • 项目类别:
The XP Variant: A Human Mutator Gene for UV Damage
XP 变体:导致紫外线损伤的人类突变基因
  • 批准号:
    6769587
  • 财政年份:
    1998
  • 资助金额:
    $ 18.51万
  • 项目类别:
The XP Variant: A Human Mutator Gene for UV Damage
XP 变体:导致紫外线损伤的人类突变基因
  • 批准号:
    6608083
  • 财政年份:
    1998
  • 资助金额:
    $ 18.51万
  • 项目类别:

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