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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 在细胞内部，DNA受到外源环境毒素和细胞代谢产物的持续攻击，这些损伤会产生各种共价核碱酶修饰。这些病变未经矫正，可能会导致影响基因组功能几乎所有方面的突变，包括转录，DNA复制和重组，以及非基因组过程，例如细胞周期进展和凋亡。这种病变的细胞管理不善导致的突变是癌症的原因。为了应对DNA病变构成的威胁，所有细胞都进化了负责定位受损核苷酸并纠正其的修复机制。 DNA中的大多数单碱基修饰都通过基础切除修复途径（BER）的酶（糖基酶）校正。但是，甚至在碱基切除过程开始之前，修复酶都必须询问数百万个未损坏的DNA的碱基对，以定位一个受损的核碱基。干草堆问题中的经典针头。这种详尽的完整基因组搜索为DNA修复系统提供了真正的艰巨任务，该酶必须进化可以以极为准确和效率来追踪病变的酶。该次要投影利用化学，生物化学和结构生物学的结合，以更好地了解BER的酶如何在正常DNA的大量过量中识别DNA病变，以及此类病变的酶促修复的机制。