DNA POLYMERASE STRUCTURES

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。次级项目的主要支助 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 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。 真核生物具有四种B家族DNA聚合酶，Pol α、Pol β、Pol δ和Pol ζ。Pol alpha在复制的起始和早期延伸步骤中起作用。Pol α与引发酶紧密结合，因此是唯一可以通过延伸由引发酶放置的RNA引物来启动DNA合成的DNA聚合酶。Pol alpha和Pol delta参与染色体DNA的准确和有效复制。相反，Pol zeta负责人类细胞和模式生物中由DNA损伤剂诱导的几乎所有突变。这些聚合酶中的任何一种失活都是致命的，而活性的降低或不适当会导致突变和染色体异常，这是已知的癌症原因。虽然催化结构域的结构是已知的，但缺乏聚合酶辅助亚基结构的信息，妨碍了对引导和滞后DNA链合成的机制以及从精确复制模式到DNA修复模式的转换机制的理解。真核生物B家族聚合酶所有亚基的结构信息以及亚基内相互作用的可用性将从根本上改变对导致诱变和癌症的过程的理解，并将为设计调节细胞突变性的化学物质创造一个平台。

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. Eukaryotes possess four B-family DNA polymerases, Pol alpha, Pol epsilon, Pol delta and Pol zeta. Pol alpha functions in initiation and early elongation steps of replication. Pol alpha is tightly associated with a primase and hence is the only DNA polymerase that can initiate the synthesis of DNA by extending RNA primers laid by primase. Pol alpha and Pol delta are involved in accurate and efficient replication of chromosomal DNA. Contrary, Pol zeta is responsible for nearly all mutations induced by DNA damaging agents in human cells and model organisms. Inactivation of any of those polymerases is lethal, while the diminished or inappropriate activity leads to mutations and chromosomal abnormalities, the known cause of cancer. Although the structure of the catalytic domains are known, the lack of information of the structure of the polymerase accessory subunits precludes the understanding the mechanisms of leading and lagging DNA strand synthesis, as well as the mechanisms of switch from accurate replication mode to DNA repair mode. The availability of structural information on all subunits of eukaryotic B family polymerases and interactions within the subunits will radically change the understanding of the processes leading to mutagenesis and cancer and will create a platform for the design of chemicals regulating cell mutability.