DNA Repair in Human Cancer-Prone Genetic Diseases

人类易患癌症的遗传疾病中的 DNA 修复

• 批准号: 6761422
• 负责人: KENNETH H KRAEMER
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6761422
• 关键词: 13 cis retinoate; DNA repair; aging; cancer prevention; cancer risk; cellular oncology; chemoprevention; clinical research; environment related neoplasm /cancer; family genetics; genetic disorder; human subject; human tissue; melanoma; molecular oncology; neoplasm /cancer genetics; nevus; plasmids; radiation carcinogen; radiation carcinogenesis; ultraviolet radiation; xeroderma pigmentosum

The laboratory is studying molecular, cellular and clinical abnormalities in human cancer-prone genetic diseases. Current studies are focusing on xeroderma pigmentosum (XP) a cancer-prone genetic disease with cellular hypersensitivity to environmental agents. We developed new assays using plasmids to measure DNA repair and mutagenesis at the molecular level in human cells and to assign cells to XP complementation groups. We found that the XPC protein leads to selective repair of UV-induced cyclobutane pyrimidine dimers in DNA. We identified several unusual XP patients. Cells from a patient with the rare xeroderma pigmentosum/ Cockayne syndrome complex with severe clinical symptoms of Cockayne syndrome had XP-G DNA repair defect leading to loss of the XPG gene. A patient with mild XP symptoms had a partially functional mutation in the XPG gene. An unusual XP-C patient had neurological abnormalities and a metabolic defect (hypoglycinemia) associated with a splice mutation. We found a common polymorphism in an intron in of the XPC gene in normal donors. Chemoprevention of skin cancer in XP with oral 13-cis retinoic acid was found to be effective in preventing skin cancers but very toxic. The lowest effective dose varied in different patients.

该实验室正在研究易人癌症遗传疾病的分子，细胞和临床异常。目前的研究集中在邻顽固的遗传疾病上，对环境药物的细胞超敏反应。 我们使用质粒开发了新的测定法，以测量人类细胞分子水平的DNA修复和诱变，并将细胞分配给XP互补组。我们发现XPC蛋白会导致对DNA中紫外线诱导的环丁烷嘧啶二聚体的选择性修复。我们确定了几个不寻常的XP患者。来自稀有的心虫色素色素/ Cockayne综合征复合物的患者的细胞患有Cockayne综合征严重的临床症状的细胞患有XP-G DNA修复缺陷，导致XPG基因丧失。轻度XP症状的患者在XPG基因中具有部分功能性突变。一个不寻常的XP-C患者患有神经系统异常和与剪接突变有关的代谢缺陷（低血糖）。我们在正常供体的XPC基因内含子中发现了共同的多态性。 发现XP中皮肤癌的化学预防发现口服13-钙视黄酸可以有效预防皮肤癌，但毒性非常毒。不同患者的有效剂量最低剂量有所不同。