STRUCTURE AND FUNCTION OF DNA POLYMERASE BETA

DNA 聚合酶 Beta 的结构和功能

• 批准号: 2459628
• 负责人: JOSEPH KRAUT
• 金额: $ 20.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2459628
• 关键词: DNA; DNA directed DNA polymerase; DNA repair; X ray crystallography; cofactor; crystallization; deoxyribonucleoside triphosphate; divalent cations; enzyme mechanism; enzyme structure; enzyme substrate analog; enzyme substrate complex; light scattering; magnesium; mutant; oligonucleotides; vanadium

The broad, long-term objective of this project is to attain an in-depth understanding of the molecular-structural basis of DNA/RNA polymerase catalytic activity and function. To this end the project will focus on the DNA polymerase beta of both human and rat, primarily using the technique of X-ray crystallography to visualize, at atomic resolution, the molecular structures of complexes in which the enzyme is bound to a range of synthetic DNA template-primer segments and nucleoside triphosphate monomers. Vertebrate DNA polymerase beta provides an excellent target for such studies as it is the smallest and functionally simplest of polymerases, but one which nevertheless bears an obvious family resemblance to the polymerase domains of larger, more complex enzymes. Template directed polymerization of RNA/DNA, in other words the polymerase reaction, is the most fundamental of biological processes. It is essential to cellular maintenance and replication. The cellular role of polymerase beta in particular is repair of a common type genomic error, which results in short gaps in one DNA strand that must be filled in by this enzyme. Accumulated errors in DNA, that is accumulated somatic mutations, are according to one widely accepted working hypothesis the root cause of most cancers and perhaps even of the aging process. A basic understanding of polymerase action in molecular terms, therefore, could conceivably lead some day to techniques for slowing the somatic mutation rate, with profoundly beneficial medical consequences.

该项目的广泛长期目标是达到深入 理解DNA/RNA聚合酶的分子结构基础 催化活性和功能。 为此，项目将重点放在 人和大鼠的DNA聚合酶β，主要使用 X射线晶体学的技术可视化原子分辨率 酶结合到范围的复合物的分子结构 合成DNA模板片段和三磷酸核苷 单体。 脊椎动物DNA聚合酶β为 这样的研究是最小，功能最简单的研究 聚合酶，但仍然有一个明显的家庭 与较大，更复杂酶的聚合酶结构域相似。 RNA/DNA的模板定向聚合，换句话说，聚合酶 反应是生物过程中最基本的。 这是 细胞维护和复制至关重要。 细胞的角色 聚合酶β特别是修复常见的基因组误差， 这导致一条DNA链的空白很短，必须填充 这种酶。 在DNA中累积错误，这是累积的体细胞 突变，根据一个广泛接受的工作假设 大多数癌症甚至衰老过程的根本原因。 基本 因此，以分子术语了解聚合酶作用可以 可以想象，有一天会导致减慢体突变的技术 比率，具有深远的医疗后果。