UNDERSTANDING THE BROAD SUBSTRATE SPECIFICITY OF ALKA AT THE ATOMIC LEVEL

在原子水平上了解 ALKA 的广泛底物特异性

• 批准号: 8361670
• 负责人: GREGORY Lawrence VERDINE
• 金额: $ 0.29万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8361670
• 关键词: Affect; Apoptosis; Base Excision Repairs; Base Pairing; Biochemistry; Cancer Etiology; Cell Cycle Progression; Cells; Charge; Chemistry; DNA; DNA Repair; DNA biosynthesis; DNA lesion; Enzymes; Excision; Funding; Genetic Recombination; Genetic Transcription; Genome; Grant; Left; Lesion; Modification; Mutation; National Center for Research Resources; Needles; Nucleotides; Pathway interactions; Principal Investigator; Process; Research; Research Infrastructure; Resources; Source; Substrate Specificity; System; Toxic Environmental Substances; United States National Institutes of Health; base; cost; non-genomic; nucleobase; repair enzyme; repaired; structural biology

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Inside cells, DNA is under constant attack by exogenous environmental toxins and cellular metabolites, insults that can produce various covalent nucleobase modifications. Left uncorrected, these lesions can cause mutations affecting nearly all aspects of genome function, including transcription, DNA replication and recombination, and also non-genomic processes such as cell cycle progression and apoptosis. The mutations that result from cellular mismanagement of such lesions are the cause of cancer. To counter the threat posed by DNA lesions, all cells have evolved repair mechanisms charged with the responsibility for locating damaged nucleotides and correcting them. Most single base modifications in DNA are corrected by enzymes (glycosylases) of the base excision repair pathway (BER). Even before the base excision process can begin, however, the repair enzymes must interrogate millions of base pairs of undamaged DNA in order to locate one damaged nucleobase; a classic needle in the haystack problem. This exhaustive full genome search presents a truly formidable task for the DNA repair system, which must evolve enzymes that can track down lesions with exceptional accuracy and efficiency. This subproject utilizes a combination of chemistry, biochemistry, and structural biology to better understand how the enzymes of the BER identify DNA lesions within the vast excess of normal DNA, as well as the mechanisms of the enzymatic repair of such lesions.

该子项目是利用资源的众多研究子项目之一 由 NIH/NCRR 资助的中心拨款提供。子项目的主要支持 并且子项目的主要研究者可能是由其他来源提供的， 包括其他 NIH 来源。 子项目可能列出的总成本 代表子项目使用的中心基础设施的估计数量， NCRR 赠款不直接向子项目或子项目工作人员提供资金。 在细胞内部，DNA 不断受到外源环境毒素和细胞代谢物的攻击，这些损伤会产生各种共价核碱基修饰。如果不加以纠正，这些病变可能会导致突变，影响基因组功能的几乎所有方面，包括转录、DNA 复制和重组，以及细胞周期进程和细胞凋亡等非基因组过程。由于细胞对此类病变处理不当而产生的突变是癌症的原因。为了应对 DNA 损伤带来的威胁，所有细胞都进化出了修复机制，负责定位受损的核苷酸并进行纠正。 DNA 中的大多数单碱基修饰均通过碱基切除修复途径 (BER) 的酶（糖基化酶）进行纠正。然而，即使在碱基切除过程开始之前，修复酶也必须询问未受损 DNA 的数百万个碱基对，以便找到一个受损的核碱基；典型的大海捞针问题。这种详尽的全基因组搜索对 DNA 修复系统来说是一项真正艰巨的任务，它必须进化出能够以极高的准确性和效率追踪病变的酶。该子项目结合化学、生物化学和结构生物学，更好地了解 BER 的酶如何识别大量正常 DNA 中的 DNA 损伤，以及酶修复此类损伤的机制。