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: 7385856
• 负责人: RANDY J LEGERSKI
• 金额: $ 152.32万
• 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 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7385856
• 关键词: Processing; Complex; Lesions; Mammalian; Genome

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.

尽管诱导这些病变的化合物对人类健康的重要性，但对哺乳动物细胞中复杂病变特别是链间交联（ICL）被去除或修复的机制知之甚少。这些化合物存在于食品中，作为哺乳动物代谢的副产物产生，具有高度毒性和致突变性。相反，这些药物中的一些也被用作高活性抗肿瘤剂。本申请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学和加强化疗方案具有重要价值。ICL修复机制的拟议解剖将包括诱变和非诱变途径，以及从损伤识别到螺旋完整性恢复的最后阶段的完整修复过程。生物化学和遗传学的方法将被用来确定ICL修复的多个途径的分子细节。此外，本申请的另一个目的是探索ICL诱导化合物作为在哺乳动物中增强重组和诱变的方法的潜在用途。 细胞。具体而言，将采用三链体技术将ICL导向特定的遗传靶标。如果成功的话，这些方法可以在基因操作方面产生重大的技术和治疗进展。