Processing of Complex Lesions in the Mammalian Genome

哺乳动物基因组中复杂损伤的处理

• 批准号: 7045959
• 负责人: RANDY J LEGERSKI
• 金额: $ 152.69万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-21 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7045959
• 关键词: DNA repair; crosslink

The mechanisms by which complex lesions particularly interstrand cross-links (ICLs) are removed or repaired in mammalian cells are poorly understood despite the importance of compounds that induce these lesions to human health. These compounds which are present in foodstuffs and produced as byproducts of mammalian metabolism, are highly toxic and mutagenic. Conversely, some of these drugs are also employed as highly active anti-tumor agents. The long term objectives of this application are a highly focused effort, involving four projects and three cores, to elucidate the molecular mechanisms of repair of ICLs with the anticipation that the knowledge gained from these studies will be of significant value to an understanding of both the etiology of tumorigenesis and the enhancement of chemotherapeutic regimens. This proposed dissection of the mechanisms of ICL repair will encompass both mutagenic and non-mutagenic pathways, as well as the complete process of repair from lesion recognition to the final stages of restoration of helical integrity. Both biochemical and genetic approaches will be employed to ascertain the molecular details of the multiple pathways of ICL repair. In addition, another objective of this application is to explore potential uses of ICL inducing compounds as a methodology to enhance recombination and mutagenesis in mammalian ceils. Specifically, the use of triplex technology will be employed to direct ICLs to a particular genetic target. If successful, these approaches could yield significant technical and therapeutic advances in genetic manipulation.

尽管具有诱导这些病变的化合物对人类健康的重要性，但在哺乳动物细胞中除去或修复了复杂的病变特别链跨链接（ICL）的机制。这些化合物存在于食品中，并作为哺乳动物代谢的副产品产生，具有剧毒和诱变。相反，其中一些药物也被用作高活性的抗肿瘤剂。该应用的长期目标是高度集中的努力，涉及四个项目和三个核心，以阐明使用ICL修复的分子机制 预期从这些研究中获得的知识将对理解肿瘤发生的病因和化学治疗方案的增强具有重要价值。 ICL修复机制的拟议解剖将涵盖诱变和非毒素途径，以及从病变识别到恢复螺旋完整性的最后阶段的完整修复过程。将采用生化方法和遗传方法来确定ICL修复多种途径的分子细节。此外，此应用的另一个目的是探索ICL诱导化合物作为增强哺乳动物重组和诱变的方法的潜在用途 天花板。具体而言，将使用三元技术将ICL引导到特定的遗传靶标。如果成功，这些方法可能会在遗传操作中产生重大的技术和治疗进步。