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.

该实验室正在研究人类易患癌症的遗传疾病的分子、细胞和临床异常。目前的研究重点是着色性干皮病 (XP)，这是一种易患癌症的遗传性疾病，细胞对环境因素过敏。 我们开发了新的检测方法，使用质粒在人类细胞的分子水平上测量 DNA 修复和诱变，并将细胞分配到 XP 互补组。我们发现 XPC 蛋白导致 DNA 中紫外线诱导的环丁烷嘧啶二聚体的选择性修复。我们发现了几位不寻常的 XP 患者。来自患有罕见色素性干皮病/科凯恩综合征且具有严重科凯恩综合征临床症状的患者的细胞具有 XP-G DNA 修复缺陷，导致 XPG 基因丢失。一名患有轻度 XP 症状的患者的 XPG 基因存在部分功能性突变。一名不寻常的 XP-C 患者患有神经系统异常和与剪接突变相关的代谢缺陷（低甘氨酸血症）。我们在正常供体的 XPC 基因的内含子中发现了常见的多态性。 XP 中口服 13-顺式视黄酸可有效预防皮肤癌，但毒性很大。不同患者的最低有效剂量有所不同。