FIDELLITY OF HUMAN POLYMERASE EPSILON

人类聚合酶 Epsilon 的保真度

基本信息

  • 批准号:
    8168375
  • 负责人:
  • 金额:
    $ 8.88万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2004
  • 资助国家:
    美国
  • 起止时间:
    2004-09-17 至 2011-07-31
  • 项目状态:
    已结题

项目摘要

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. Spontaneous mutation rates in normal somatic mammalian cells are such that less than one mutation occurs per genome duplication. By contrast, cancer cells are characterized by having unstable genomes and recent genome-wide sequencing of tumor-derived cell lines has revealed thousands of mutations throughout their genome. DNA replication is a normally highly faithful process that plays an essential role in maintaining low spontaneous mutation rates. Three DNA polymerases (Pols), Pols a, d and e, are responsible for the vast majority of replicative DNA synthesis in eukaryotes. Pols d and e have been studied in model organisms and are highly accurate due to having a high replication fidelity combined with an intrinsic proofreading exonuclease activity. Mutations in yeast and mouse Pol e that reduce this high replication fidelity lead to increases in mutation rates and tumorigenesis. The contributions to genome stability and replication fidelity in human cells are currently unknown for human Pol e. The goal of this project is to develop human cell lines with the endogenous copies of Pol e changed to residues demonstrated to reduce in vitro replication fidelity. We will employ existing recombinant adeno-associated virus technology to generate knock-in alleles of human Pol e in mismatch repair-deficient and matched mismatch repair-corrected human cell lines. We will first characterize mutation rates and then determine patterns of mutations by sequencing the HPRT locus. We are currently working on characterizing the in vitro replication fidelity of human Pol e. Additionally, we are developing a system to express and purify mutants of Pol e and characterize the changes to in vitro replication fidelity caused by these mutator mutations. Combined with the results from this project, we hope to correlate changes to mutation rates and patterns caused by mutator mutants in vivo to the pattern of mutations made by those same mutants in vivo and measure directly the contribution of human Pol e to genome stability.
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。 在正常的体细胞哺乳动物细胞中,自发突变率是这样的:每次基因组复制发生的突变不到一个。相比之下,癌细胞的特点是基因组不稳定,最近对肿瘤来源的细胞系进行的全基因组测序发现,它们的基因组中有数千个突变。DNA复制通常是一个高度忠诚的过程,在保持较低的自发突变率方面起着至关重要的作用。三种DNA聚合酶(POL),POLS a,d和e,负责真核生物中绝大多数的复制DNA合成。极点d和e已经在模型生物中进行了研究,由于具有高复制保真度和固有的校对核酸外切酶活性,因此具有高度的准确性。酵母和小鼠Pol E中降低这种高复制保真度的突变会导致突变率和肿瘤发生的增加。在人类细胞中,对基因组稳定性和复制保真度的贡献目前尚不清楚。 该项目的目标是开发内源性Pol e拷贝改变为残基的人类细胞系,证明其降低了体外复制的保真度。我们将利用现有的重组腺相关病毒技术,在错配修复缺陷和匹配的错配修复纠正的人类细胞系中产生人Pol e的敲入等位基因。我们将首先确定突变率的特征,然后通过对HPRT基因座进行测序来确定突变模式。 我们目前正在研究人Pol e的体外复制保真度。此外,我们正在开发一种系统来表达和纯化Pol e的突变体,并表征这些突变子突变对体外复制保真度的影响。结合这一项目的结果,我们希望将体内突变体引起的突变率和突变模式的变化与这些相同突变体在体内所造成的突变模式相关联,并直接测量人类极点对基因组稳定性的贡献。

项目成果

期刊论文数量(0)
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Zachary F Pursell其他文献

Zachary F Pursell的其他文献

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{{ truncateString('Zachary F Pursell', 18)}}的其他基金

Investigation of human DNA polymerase epsilon variants
人类 DNA 聚合酶 epsilon 变异体的研究
  • 批准号:
    10367753
  • 财政年份:
    2017
  • 资助金额:
    $ 8.88万
  • 项目类别:
Investigation of human DNA polymerase epsilon variants
人类 DNA 聚合酶 epsilon 变异体的研究
  • 批准号:
    10220033
  • 财政年份:
    2017
  • 资助金额:
    $ 8.88万
  • 项目类别:
Investigation of human DNA polymerase epsilon variants
人类 DNA 聚合酶 epsilon 变异体的研究
  • 批准号:
    10684642
  • 财政年份:
    2017
  • 资助金额:
    $ 8.88万
  • 项目类别:
Investigation of human DNA polymerase epsilon variants
人类 DNA 聚合酶 epsilon 变异体的研究
  • 批准号:
    9364697
  • 财政年份:
    2017
  • 资助金额:
    $ 8.88万
  • 项目类别:
Mutagenesis, tumorigenesis and human DNA polymerase epsilon
诱变、肿瘤发生和人类 DNA 聚合酶 epsilon
  • 批准号:
    9252804
  • 财政年份:
    2016
  • 资助金额:
    $ 8.88万
  • 项目类别:
Roles of Human DNA Polymearse Epsilon in Mutagenesis and Genome Stability
人类 DNA 聚合酶 Epsilon 在诱变和基因组稳定性中的作用
  • 批准号:
    7923817
  • 财政年份:
    2009
  • 资助金额:
    $ 8.88万
  • 项目类别:
Roles of Human DNA Polymearse Epsilon in Mutagenesis and Genome Stability
人类 DNA 聚合酶 Epsilon 在诱变和基因组稳定性中的作用
  • 批准号:
    8118527
  • 财政年份:
    2009
  • 资助金额:
    $ 8.88万
  • 项目类别:
Roles of Human DNA Polymearse Epsilon in Mutagenesis and Genome Stability
人类 DNA 聚合酶 Epsilon 在诱变和基因组稳定性中的作用
  • 批准号:
    7879695
  • 财政年份:
    2009
  • 资助金额:
    $ 8.88万
  • 项目类别:
FIDELLITY OF HUMAN POLYMERASE EPSILON
人类聚合酶 Epsilon 的保真度
  • 批准号:
    8360726
  • 财政年份:
    2004
  • 资助金额:
    $ 8.88万
  • 项目类别:

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