STUDIES ON DNA POLYMERASES

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。子项目的主要支持 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， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 细胞组织持续地受到外部的破坏剂，例如阳光和化学污染物，以及内部的氧化和水解（Prakash等人，2005年）。 已经进化出多种DNA修复途径来修复所产生的损伤，但是一些损伤逃避修复并且将被复制机器遇到。 新发现的跨病变DNA合成（TLS）聚合酶允许细胞通过促进病变的复制来科普未修复的DNA损伤，否则会阻止复制叉。人类有四种这样的TLS聚合酶  Pol <$、Pol <$、Pol <$和Rev 1  每一个都有独特的DNA损伤旁路和保真度特征。 波尔例如，其独特之处在于其通过在二聚体对面插入两个腺嘌呤而通过UV诱导的顺式-顺式环丁烷胸腺嘧啶-胸腺嘧啶（T-T）二聚体进行复制的熟练能力。 人类Pol？的突变导致了一种遗传性癌症易感性疾病，即着色性干皮病（XP-V）的变异形式。 因此，Pol是第一个被证明可以作为肿瘤抑制因子的DNA聚合酶。另一方面，Pol <$在未受损DNA上的错配引物末端的延伸和病变旁路的延伸步骤中是专门的。为了了解这些聚合酶如何与“经典”聚合酶交换，我们还开始了对真核生物中滞后/前导链聚合酶的研究。

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. Cellular tissue is continually subjected to damaging agents such as sunlight and chemical pollutants externally, and oxidation and hydrolysis internally (Prakash et al., 2005). A variety of DNA repair pathways have evolved to repair the resulting lesions, but some lesions escape repair and will be encountered by the replication machinery. The newly discovered translesion DNA synthesis (TLS) polymerases allow cells to cope with unrepaired DNA damage by promoting replication through lesions that would otherwise stall the replication fork. Humans have four such TLS polymerases  Pol¿, Pol¿, Pol¿, and Rev1  each with a unique DNA damage bypass and fidelity profile. Pol¿, for example, is unique in its proficient ability to replicate through a UV-induced cis-syn cyclobutane thymine-thymine (T-T) dimer) by inserting two adenines opposite the dimer. Mutations in human Pol¿ are responsible for an inherited cancer-prone disorder, the variant form of xeroderma pigmentosum (XP-V). Pol¿ is, thus, the first DNA polymerase demonstrated to act as a tumor suppressor. Pol¿, on the other hand, is specialized in the extension of mispaired primer termini on undamaged DNAs, and in the extension step of lesion bypass. To understand how these polymerases exchange with "classical" polymerases, we have also initiated studies on the lagging/leading strand polymerases ¿ and ¿ in eukaryotes.