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首页> 外文学位 >Immunoglobulin switch mu sequence causes RNA polymerase II accumulation and reduces dA hypermutation.
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Immunoglobulin switch mu sequence causes RNA polymerase II accumulation and reduces dA hypermutation.

机译：免疫球蛋白切换mu序列引起RNA聚合酶II积累并减少dA超突变。

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摘要

Repetitive DNA sequences in the immunoglobulin switch mu region form RNA-containing secondary structures and undergo hypermutation by activation-induced deaminase (AID). To examine how DNA structure affects transcription and hypermutation, we mapped the position of RNA polymerase II molecules and mutations across a 5-kb region spanning the intronic enhancer to the constant mu gene. For RNA polymerase II, the distribution was determined by nuclear run-on and chromatin immunoprecipitation assays in B cells from uracil-DNA glycosylase (UNG)--deficient mice stimulated ex vivo. RNA polymerases were found at a high density in DNA flanking both sides of a 1-kb repetitive sequence that forms the core of the switch region. The pileup of polymerases was similar in unstimulated and stimulated cells from Ung-/- and Aid-/- Ung -/- mice but was absent in cells from mice with a deletion of the switch region. For mutations, DNA was sequenced from Ung -/- B cells stimulated in vivo. Surprisingly, mutations of A nucleotides, which are incorporated by DNA polymerase eta, decreased 10-fold before the repetitive sequence, suggesting that the polymerase was less active in this region. We propose that altered DNA structure in the switch region pauses RNA polymerase II and limits access of DNA polymerase eta during hypermutation.
机译：免疫球蛋白转换区的重复DNA序列形成含RNA的二级结构，并通过激活诱导的脱氨酶（AID）进行超突变。为了检查DNA结构如何影响转录和超突变，我们绘制了RNA聚合酶II分子的位置和跨越内含子增强子到恒定mu基因的5-kb区域的突变。对于RNA聚合酶II，通过核试验和染色质免疫沉淀测定法确定了离体刺激的尿嘧啶DNA糖基化酶（UNG）缺陷小鼠B细胞中的分布。在形成开关区域核心的1kb重复序列两侧的DNA中，发现了高密度的RNA聚合酶。在Ung-/-和Aid-/-Ung-/-小鼠的未刺激和刺激的细胞中，聚合酶的堆积相似，但是在缺失开关区域的小鼠的细胞中却没有。对于突变，从体内刺激的Ung-/-B细胞中测序DNA。出人意料的是，DNA聚合酶eta掺入的A核苷酸突变在重复序列之前降低了10倍，这表明该区域的聚合酶活性较低。我们建议改变的DNA结构在开关区域暂停RNA聚合酶II，并限制DNA聚合酶eta在超突变过程中的访问。

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  • 作者

    Rajagopal, Deepa.;

  • 作者单位

    University of Maryland, Baltimore.;

  • 授予单位 University of Maryland, Baltimore.;
  • 学科 Health Sciences Immunology.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 141 p.
  • 总页数 141
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 地球物理学;
  • 关键词

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