STUDIES ON DNA POLYMERASES

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 细胞组织不断受到外部阳光和化学污染物以及内部氧化和水解等破坏性因素的影响(Prakash等人，2005年)。各种DNA修复途径已经进化到修复所产生的损伤，但一些损伤逃脱修复，并将遇到复制机制。新发现的跨损伤DNA合成(TLS)聚合酶允许细胞通过损伤促进复制，从而应对未修复的DNA损伤，否则复制叉会停滞。人类有四个这样的TLS聚合酶Pol？和Rev1，每个都有独特的DNA损伤旁路和保真度特征。例如，POL的独特之处在于其通过紫外线诱导的顺式环丁烷胸腺嘧啶-胸腺嘧啶(T-T)二聚体通过插入两个与二聚体相对的腺嘌呤进行复制的熟练能力。人类POL的突变是一种遗传性癌症易感疾病的原因，这种疾病是变种形式的着色性干皮病(XP-V)。因此，POL？是第一个被证明发挥肿瘤抑制作用的DNA聚合酶。另一方面，POL专门研究未受损DNA上错配对的引物末端的延伸，以及病变旁路的延伸步骤。为了了解这些聚合酶如何与“经典”聚合酶交换，我们还启动了对真核生物中领先/滞后链聚合酶的研究。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 leading/lagging strand polymerases in eukaryotes.