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DNA repair systems and cellular responses to DNA damage.

机译：DNA修复系统和细胞对DNA损伤的反应。

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摘要

Within the context of a multicellular organism, accumulation of genetic mutations can lead to tumor formation. In order to avoid such deleterious events, each cell is equipped with a series of DNA damage sensors and repair systems to deal with the DNA lesions that can lead to such mutations. Joined to these repair systems are additional cellular responses, such as cell cycle arrest, providing the cell time for repair, or if need be, apoptosis, removing a cell from the population if the repair systems are not sufficient to deal with the DNA damage. The deleterious effects of deficiencies in components of the repair and cell response pathways are evident in the human diseases associated with inherited and spontaneous mutations in genes encoding these factors.; This dissertation attempts to elucidate the specific roles of certain components of the DNA mismatch repair (MMR) and DNA double strand break (DSB) repair systems. In addition, we examined the link between their role in repair and other cellular responses to DNA damage. Employing a CHO model system, the role of mammalian MSH3, with respect to its function in mismatch repair, was studied. In agreement with studies of the human homolog, and the lack of disease associated with its mutation, we found no consistent link between the loss of MSH3 and the common cellular phenotypes associated with MMR deficiency. The MMR deficient HCT116 colon tumor cell line demonstrates the characteristics of a NMR deficient cell line, presumably due to the specific deficiency of the MMR protein hMLH1. Employing an inducible hMLH1 expression system, we were able to correct the MMR deficiency phenotype of this tumor line and, interestingly, only a small amount of hMLH1 expression was necessary for complementation. Finally, we studied the role of the Rad51 paralog XRCC3 in the homologous recombination associated DSB repair system. Employing a CHO model system, we found that despite the expected increase in sensitivity to camptothecin, a DNA double-strand break inducing agent, the XRCC3 deficient cell line irs1SF had a reduced apoptotic response. This suggests a link between the processes of homologous recombination and induction of apoptosis.
机译：在多细胞生物的背景下，遗传突变的积累可导致肿瘤形成。为了避免此类有害事件，每个细胞都配备了一系列DNA损伤传感器和修复系统，以处理可能导致此类突变的DNA损伤。与这些修复系统相连的是其他细胞反应，例如细胞周期停滞，提供了修复所需的细胞时间，或者在必要时提供凋亡，如果修复系统不足以应对DNA损伤，则可以从种群中移出细胞。在与编码这些因子的基因中的遗传性和自发性突变有关的人类疾病中，修复和细胞反应途径的成分缺乏的有害影响是显而易见的。本文试图阐明DNA错配修复（MMR）和DNA双链断裂（DSB）修复系统某些成分的具体作用。此外，我们检查了它们在修复中的作用与其他细胞对DNA损伤的反应之间的联系。利用CHO模型系统，研究了哺乳动物MSH3在失配修复中的作用。与人类同源物的研究相一致，以及缺乏与突变相关的疾病，我们发现MSH3的丧失与MMR缺乏症相关的常见细胞表型之间没有一致的联系。 MMR缺陷型HCT116结肠肿瘤细胞系表现出NMR缺陷型细胞系的特征，大概是由于MMR蛋白hMLH1的特定缺陷。使用可诱导的hMLH1表达系统，我们能够纠正该肿瘤细胞系的MMR缺乏表型，有趣的是，仅需少量的hMLH1表达即可进行互补。最后，我们研究了Rad51旁系同源XRCC3在同源重组相关DSB修复系统中的作用。使用CHO模型系统，我们发现尽管对喜树碱（一种DNA双链断裂诱导剂）的敏感性预期有所提高，但XRCC3缺陷型细胞irs1SF的凋亡反应却有所降低。这表明同源重组过程与凋亡诱导之间存在联系。

著录项

  • 作者

    Hinz, John Michael.;

  • 作者单位

    The University of Utah.;

  • 授予单位 The University of Utah.;
  • 学科 Biology Molecular.; Biology Cell.
  • 学位 Ph.D.
  • 年度 2001
  • 页码 168 p.
  • 总页数 168
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 分子遗传学;细胞生物学;
  • 关键词

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