Transcription-coupled repair of Oxidative DNA damage in vivo

体内氧化 DNA 损伤的转录偶联修复

基本信息

  • 批准号:
    8061606
  • 负责人:
  • 金额:
    $ 25.21万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-06-01 至 2013-09-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): DNA damage that blocks transcription can prevent the expression of essential genes, leading to mutations, apoptosis, or necrotic cell death. Transcription-coupled repair is a cellular process by which some forms of DNA damage are repaired more rapidly from transcribed strands of active genes than from nontranscribed strands or the overall genome. Cockayne syndrome patients are characterized by developmental and neurological deficiencies and are specifically defective in the process transcription-coupled repair. It has been widely speculated that the transcription-coupled repair of oxidative-DNA lesions, in particular, may be an underlying cause of the underlying developmental and neurological deficiencies in Cockayne's syndrome, and may be involved in other diseases that involve the progressive loss of neurological function, such as Parkinsons and Alzheimer's disease. However, the rapid kinetics of oxidative repair relative to transcription, and the apoptotic cascade induced by reactive oxygen and stalled transcription machinery have made it technically difficult to address this hypothesis in mammalian cells, despite intense efforts. We therefore, propose to test this hypothesis directly in the model organism of E.coli, where the process of transcription-coupled repair and oxidative DNA repair are highly conserved. We show that the low complexity genome, well-characterized transcriptional operons, and use of purified DNA glycosylases and isogenic mutants allow us to overcome the obstacles arising in human cell cultures to detect and definitively answer this important question. We hypothesize that specific oxidative DNA lesions are repaired in a transcription-coupled manner in vivo. We further hypothesize that lesions that block RNA polymerase will be subject to transcription-coupled repair, whereas nonblocking lesions will not, and that the process will depend on a number of gene products including, a coupling factor- Mfd, nucleotide excision repair, and specific DNA glycosylases. To test these hypotheses, we will 1) use purified DNA glycosylases with known substrate specificities to measure the repair kinetics of different oxidative DNA lesions in vivo; 2) examine the repair rates of different classes of oxidative damage, 8-oxoguanine, thymine glycol, and others, to identify which classes of oxidative lesions are repaired in a transcription-coupled manner; 3) measure the repair rate of oxidative lesions and recovery of RNA synthesis in isogenic mutants that lack nucleotide excision repair, oxidative DNA glycosylases, or Mfd. PUBLIC HEALTH RELEVANCE: The results from this project will enhance our understanding of the roles of transcription and transcription-coupled repair in processing oxidative DNA damage that have been implicated in human disease. Reactive oxygen species are directly or indirectly associated with a range of human hereditary diseases ranging from Parkinsons and Alzheimers, to amyotrophic lateral sclerosis and Friedreich's ataxia, to Fanconi anemia and Cockayne syndrome. In addition, there is increasing evidence to suggest reactive oxygen species play a significant role in the spontaneous cancers and aging. Since both oxidative DNA damage and transcription arrest generate strong signals for apoptosis, the research may lead to novel modes of chemotherapy, involving selective inhibition of transcription-coupled repair in target cells combined with administration of transcription-blocking drugs or antioxidants.
描述(由申请人提供):阻断转录的DNA损伤可以防止基本基因的表达,从而导致突变,凋亡或坏死细胞死亡。转录耦合修复是一种细胞过程,通过该过程,通过该过程,从活性基因的转录链中,与非转录链或整体基因组相比,某些形式的DNA损伤更快地修复了。 Cockayne综合征患者的特征是发育和神经功能缺陷,并且在转录偶联修复过程中特别有缺陷。人们普遍猜测,尤其是氧化DNA病变的转录偶联修复可能是Cockayne综合征中潜在的发育和神经系统缺陷的根本原因,并且可能涉及其他疾病,涉及涉及诸如帕克森和艾尔兹氏病的神经学丧失。然而,尽管付出了巨大的努力,但相对于转录的氧化修复的快速动力学以及由反应性氧和停滞的转录机制引起的凋亡级联反应使在哺乳动物细胞中的这种假设很难解决。因此,我们建议直接在大肠杆菌模型生物中检验该假设,其中转录耦合修复和氧化DNA修复的过程是高度保守的。我们表明,低复杂性基因组,特征良好的转录操纵子以及纯化的DNA糖基酶和同基因突变体的使用使我们能够克服人类细胞培养物在检测并确定回答这个重要问题的障碍。我们假设特定的氧化DNA病变以体内的转录耦合方式修复。我们进一步假设,阻断RNA聚合酶的病变将经过转录耦合修复,而非阻塞病变不会进行,并且该过程将取决于许多基因产物,包括偶联因子MFD,核苷酸固醇切除率和特定DNA糖基酶。为了检验这些假设,我们将1)使用具有已知底物特异性的纯化DNA糖基化酶来测量体内不同氧化DNA病变的修复动力学; 2)检查不同类别的氧化损伤,8-氧化氨酸,胸腺甘氨酸等的修复率,以鉴定以转录偶联方式修复哪种氧化病变; 3)测量缺乏核苷酸切除修复,氧化性DNA糖基化酶或MFD的等源性突变体中氧化病变的修复率和RNA合成的恢复。 公共卫生相关性:该项目的结果将增强我们对转录和转录偶联修复在处理与人类疾病有关的氧化DNA损伤中的作用的理解。活性氧与从帕金森氏症和阿尔茨海默氏症,肌萎缩性侧面硬化症和弗里德雷希的共济失调,到芬科尼尼贫血和cockayne综合征的一系列人类遗传疾病直接或间接相关。此外,越来越多的证据表明活性氧在自发性癌症和衰老中起着重要作用。 由于氧化性DNA损伤和转录停滞都会引起凋亡的强信号,因此该研究可能导致新型化疗模式,涉及对靶细胞的选择性抑制转录偶联修复,并结合施用转录阻滞药物或抗氧化剂。

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Escherichia coli Fpg glycosylase is nonrendundant and required for the rapid global repair of oxidized purine and pyrimidine damage in vivo.
大肠杆菌 Fpg 糖基化酶是非冗余的,是体内氧化嘌呤和嘧啶损伤快速整体修复所必需的。
  • DOI:
    10.1016/j.jmb.2011.05.004
  • 发表时间:
    2011
  • 期刊:
  • 影响因子:
    5.6
  • 作者:
    Schalow,BrandyJ;Courcelle,CharmainT;Courcelle,Justin
  • 通讯作者:
    Courcelle,Justin
RecBCD is required to complete chromosomal replication: Implications for double-strand break frequencies and repair mechanisms.
  • DOI:
    10.1016/j.dnarep.2015.04.018
  • 发表时间:
    2015-08
  • 期刊:
  • 影响因子:
    3.8
  • 作者:
    Courcelle J;Wendel BM;Livingstone DD;Courcelle CT
  • 通讯作者:
    Courcelle CT
Mfd is required for rapid recovery of transcription following UV-induced DNA damage but not oxidative DNA damage in Escherichia coli.
Mfd 是紫外线诱导的 DNA 损伤后转录快速恢复所必需的,但大肠杆菌中的氧化性 DNA 损伤则不需要 Mfd。
  • DOI:
    10.1128/jb.06725-11
  • 发表时间:
    2012
  • 期刊:
  • 影响因子:
    3.2
  • 作者:
    Schalow,BrandyJ;Courcelle,CharmainT;Courcelle,Justin
  • 通讯作者:
    Courcelle,Justin
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Justin Courcelle其他文献

Justin Courcelle的其他文献

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{{ truncateString('Justin Courcelle', 18)}}的其他基金

Eukaryotic Completion of DNA Replication
真核生物完成 DNA 复制
  • 批准号:
    10412150
  • 财政年份:
    2022
  • 资助金额:
    $ 25.21万
  • 项目类别:
Replication-Coupled Repair: a mechanism for surviving UV irradiation
复制耦合修复:一种在紫外线照射下存活的机制
  • 批准号:
    10575759
  • 财政年份:
    2022
  • 资助金额:
    $ 25.21万
  • 项目类别:
Mechanism of DNA interstrand crosslink repair in vivo
体内DNA链间交联修复机制
  • 批准号:
    8958561
  • 财政年份:
    2015
  • 资助金额:
    $ 25.21万
  • 项目类别:
R15 AREA: Replication in the Presence of Oxidative DNA damage
R15 区域:存在氧化 DNA 损伤时的复制
  • 批准号:
    8290917
  • 财政年份:
    2012
  • 资助金额:
    $ 25.21万
  • 项目类别:
Transcription-coupled repair of Oxidative DNA damage in vivo
体内氧化 DNA 损伤的转录偶联修复
  • 批准号:
    7875831
  • 财政年份:
    2010
  • 资助金额:
    $ 25.21万
  • 项目类别:

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