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: 8212040
• 负责人: RANDY J LEGERSKI
• 金额: $ 155.09万
• 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 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212040
• 关键词: Address; Base Excision Repairs; Biochemical; Biochemical Pathway; CHEK2 gene; CHES1 gene; Cell Cycle Checkpoint; Cells; Chemotherapy-Oncologic Procedure; Cisplatin; Clinical Medicine; Complex; Cyclophosphamide; DNA Damage; DNA Interstrand Crosslinking; DNA Repair; DNA-Directed DNA Polymerase; Development; Dissection; Double Strand Break Repair; Effectiveness; Etiology; Excision; Future; Genetic; Genetic Recombination; Goals; Health; Human; Individual; Investigation; Joints; Knowledge; Lesion; MLH1 gene; Mammalian Cell; Melphalan; Metabolism; Methodology; Mismatch Repair; Mitomycins; Modeling; Molecular; Molecular Genetics; Molecular Target; Mutagenesis; Nucleotide Excision Repair; Pathway interactions; Pharmaceutical Preparations; Process; Proteins; Radiation; Recording of previous events; Regimen; Replication Error; Resolution; Role; S Phase; Signal Transduction; Site; Staging; Structure-Activity Relationship; System; Techniques; Technology; Therapeutic; Therapeutic Uses; adduct; antitumor agent; base; cancer therapy; crosslink; cytotoxic; design; drug efficacy; genetic manipulation; improved; killings; mammalian genome; neoplastic cell; new therapeutic target; novel; programs; repaired; research study; response; restoration; tumorigenesis

DESCRIPTION (provided by applicant): The mechanisms by which complex lesions, particularly interstrand cross-links (ICLs), are removed or repaired in mammalian cells are poorly understood despite the importance to human health of compounds that induce these lesions. These agents, 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, involving four highly integrated projects and three cores, aim 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 understanding 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. Biochemical, molecular, and genetic approaches will be employed to elucidate of [sic] the mechanistic 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 cells. Specifically, the use of triplex technology will be employed to direct ICLs to a particular genetic target. These approaches have excellent potential to yield useful technical and therapeutic advances in genetic manipulation.

描述（由申请人提供）：尽管诱导这些病变的化合物对人类健康很重要，但人们对哺乳动物细胞中复杂病变，特别是链间交联（icl）被移除或修复的机制知之甚少。这些物质存在于食品中，并作为哺乳动物代谢的副产品产生，具有高度毒性和诱变性。相反，其中一些药物也被用作高活性的抗肿瘤药物。该项目的长期目标包括四个高度整合的项目和三个核心，旨在阐明ICLs修复的分子机制，并期望从这些研究中获得的知识将对了解肿瘤发生的病因和增强化疗方案具有重要价值。本文提出的ICL修复机制的解剖将包括致突变和非致突变途径，以及从病变识别到螺旋完整性恢复的最后阶段的完整修复过程。将采用生化、分子和遗传方法来阐明ICL修复的多种途径的机制细节。此外，本申请的另一个目的是探索ICL诱导化合物作为一种增强哺乳动物细胞重组和诱变的方法的潜在用途。具体来说，将使用三重技术将ICLs定向到特定的遗传靶标。这些方法极有可能在基因操作方面产生有用的技术和治疗进展。