NUCLEOTIDE EXCISION REPAIR OF DNA TRIPLE HELICES

DNA 三重螺旋的核苷酸切除修复

• 批准号: 2024388
• 负责人: Michael M SEIDMAN
• 金额: $ 10.29万
• 依托单位: CODON PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2024388
• 关键词: DNA damage; DNA repair; adduct; cell line; chemical structure function; conformation; gene mutation; genetic transcription; molecular site; nucleic acid sequence; transfection /expression vector; triple helix

DESCRIPTION (Adapted from applicant's abstract): Mutagenesis of critical genes underlies the development of cancer and of genetic diseases. One of the major guardians against mutagenesis is the nucleotide excision repair (NER) system that repairs single base DNA adducts in an error free manner. Little is known about the activity of NER on more extensive alterations in DNA structure. The investigator has recently reported data that suggests that the NER system can recognize and process normal DNA bases present in the distorted, alternate conformation of a triple helix, a structure that is known to block transcription. In contrast to repair of conventional adducts, the process is error prone. The triplex induced mutagenesis required the function of transcription coupled repair, TCR, which is involved in the preferential repair of transcribed DNA. These data are consistent with the proposal that sequences that block transcription could trigger "gratuitous repair induced mutagenesis." Dr. Seidman proposes to use the triple helix as a novel structural probe of the NER system. The applicant will exploit the flexibility of the supF shuttle vector system and construct custom marker genes which will facilitate examination of the influence of triplex structural features on recognition by the NER system. The requirement for transcription through the triplex region for NER recognition will be determined. Then human cell lines with specific defects in repair genes will be used to define the role of individual components of the NER system in recognition and processing of triplex distortion.

描述（改编自申请人的摘要）：关键的诱变 基因是癌症和遗传疾病的发展。 之一 反对诱变的主要监护人是核苷酸切除修复 （NER）以无误差方式修复单个基本DNA加合物的系统。 关于NER对更广泛改变的活动知之甚少 DNA结构。 研究人员最近报告了建议的数据 NER系统可以识别并处理存在于 三重螺旋的扭曲的替代构象，一种结构 已知可以阻止转录。 与传统的修复相反 加合物，该过程容易发生。 三胞胎诱导的诱变 需要转录耦合修复的功能TCR，即 参与转录DNA的优先修复。 这些数据是 与阻止转录序列的提议一致 触发“免费修复诱导诱变”。 Seidman博士建议 使用三重螺旋作为NER系统的新结构探针。 这 申请人将利用SUPF穿梭矢量系统的灵活性和 构建定制标记基因，将有助于检查 三元结构特征对NER系统识别的影响。 通过三元区域转录的要求 将确定认可。 然后具有特定缺陷的人类细胞系 在维修基因中，将用于定义单个组件的作用 识别和处理三重失真的NER系统。