The initiation of mRNA degradation by the direct entry of RNase E and the degradosome with implications for non-nucleolytic gene control

RNase E 和降解体的直接进入引发 mRNA 降解,对非溶核基因控制具有影响

基本信息

  • 批准号:
    BB/I001751/1
  • 负责人:
  • 金额:
    $ 44.93万
  • 依托单位:
  • 依托单位国家:
    英国
  • 项目类别:
    Research Grant
  • 财政年份:
    2011
  • 资助国家:
    英国
  • 起止时间:
    2011 至 无数据
  • 项目状态:
    已结题

项目摘要

Many bacterial species pose a significant health-risk to humans, animals and plants, while others are an important source of nutrients and medicines including antimicrobials and anti-cancer agents. Some, including one called Escherichia coli (or E. coli for short), are used as factories for the production of therapeutics and other compounds of commercial or clinical value; much in the same way that yeast can be used to make alcohol. All organisms contain blocks of information called genes, which are passed from one generation to the next. The process by which the information in these genes is manifested in the characteristics of living organisms is called gene expression. The information in a gene is not read directly; instead, a copy called the messenger is made with a limited 'shelf life'. The shelf-life of the messenger determines how many times it can be read and, in turn, the characteristics of an organism. The stability of messengers in E. coli is the subject area of this application. More specifically, we wish to characterise a newly identified mode of recognising messengers that evidence from a number of sources indicates is pivotal to the process of initiating their degradation. We also plan to determine whether this mode of recognition can explain why messengers are highly vulnerable to degradation when they are not being read. This happens, for example, upon the binding of messengers by small RNAs, which represent an emerging class of regulator that is associated with bacterial survival and pathogenicity. In the longer term, our research may also impact the search for new antimicrobials, which is timely given the alarming rate at which resistance to antibiotics is emerging in bacterial populations. The function of E. coli RNase E is essential, so disabling its activity could be lethal to the many pathogens that contain this enzyme. Knocking out RNase E activity after E. coli has grown (in the form of a bio-factory) may also lead to the increased production of compounds of commercial and clinical value, by increasing the number of times the corresponding messengers can be read. This proposal is also relevant to synthetic biology, 'a new and growing science that focuses on re-designing and re-building natural biological systems synthetically from the ground up'. In the 32nd annual Richard Dimbleby lecture, Dr. J. Craig Venter (who is probably best known for heading the private enterprise that sequenced the human genome) outlined how bacteria could be engineered by 'human intelligence' to create renewable energy and combat climate change. This is not science fiction. Modified bacteria are already being used by DuPont to convert sugar into a new polymer that can be used to produce stain-resistant carpets and clothing. Other companies including BP are trying to adapt bacteria to make the next generation of biofuels. Genes with related functions (e.g. those that part of the same pathway or complex) can be expressed as part of the same messenger in bacteria. This ensures that all the components for a particular process are made at the same time. The ultimate goal for synthetic biologists is to be able to design systems from 'scratch' using rules learnt from nature. In these systems, the messengers will need to have a sufficient 'shelf-life' to be able to confer attributes that are desired, while at the same time not being too stable such that the information is permanent. This proposal could provide information necessary for the rational engineering of messengers encoding multiple genes such that different components can be made in different amounts.
许多细菌物种对人类、动物和植物的健康构成重大威胁,而其他细菌物种则是营养物质和药物的重要来源,包括抗菌剂和抗癌剂。其中一些,包括一种名为大肠杆菌(或简称大肠杆菌)的细菌,被用作生产治疗药物和其他具有商业或临床价值的化合物的工厂;这与酵母可以用来酿造酒精的方式很相似。所有生物体都包含被称为基因的信息块,这些信息会从一代传到下一代。这些基因中的信息在生物体的特性中表现出来的过程称为基因表达。基因中的信息不是直接读取的;相反,被称为信使的副本是在有限的“保质期”内制造的。信使的保质期决定了它可以被阅读的次数,进而决定了生物体的特征。大肠杆菌中信使的稳定性是这一应用的主题领域。更具体地说,我们希望描述一种新确定的识别信使的模式,来自多个来源的证据表明,这种模式对于启动信使退化的过程至关重要。我们还计划确定这种识别模式是否可以解释为什么信使在不被阅读时非常容易被退化。例如,这发生在信使与小RNA的结合上,小RNA代表了一种与细菌生存和致病性相关的新兴调节因子。从长远来看,我们的研究还可能影响对新抗菌剂的寻找,考虑到细菌群体中出现抗生素耐药性的惊人速度,这是及时的。大肠杆菌核糖核酸酶E的功能是必不可少的,因此禁用它的活性可能会对许多含有这种酶的病原体致命。在大肠杆菌(以生物工厂的形式)生长后敲除RNaseE活性也可能导致具有商业和临床价值的化合物的生产增加,因为它增加了相应的信使可以被阅读的次数。这一建议也与合成生物学有关,合成生物学是一门新兴的科学,专注于从头开始重新设计和重建自然生物系统。在第32届理查德·丁布尔比(Richard Dimbleby)年度讲座上,J·克雷格·文特尔(J.Craig Venter)博士(他最出名的可能是领导了一家为人类基因组测序的私营企业)概述了如何通过人类智能来改造细菌,以创造可再生能源和应对气候变化。这不是科幻小说。杜邦已经在使用改良的细菌将糖转化为一种新的聚合物,可以用来生产防沾污的地毯和服装。包括英国石油公司在内的其他公司正在努力改造细菌,以制造下一代生物燃料。具有相关功能的基因(例如,那些属于相同途径或复合体的基因)可以在细菌中作为同一信使的一部分表达。这确保了特定工艺的所有组件都是同时制造的。合成生物学家的最终目标是能够使用从自然中学习的规则从头开始设计系统。在这些系统中,信使需要有足够的“保质期”,以便能够提供所需的属性,同时又不能过于稳定,以至于信息是永久性的。这一提议可以为合理设计编码多个基因的信使提供必要的信息,从而使不同的成分可以以不同的数量制造。

项目成果

期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The first small-molecule inhibitors of members of the ribonuclease E family.
  • DOI:
    10.1038/srep08028
  • 发表时间:
    2015-01-26
  • 期刊:
  • 影响因子:
    4.6
  • 作者:
    Kime L;Vincent HA;Gendoo DM;Jourdan SS;Fishwick CW;Callaghan AJ;McDowall KJ
  • 通讯作者:
    McDowall KJ
The recognition of structured elements by a conserved groove distant from domains associated with catalysis is an essential determinant of RNase E.
  • DOI:
    10.1093/nar/gkac1228
  • 发表时间:
    2023-01-11
  • 期刊:
  • 影响因子:
    14.9
  • 作者:
    Clarke, Justin E.;Sabharwal, Kiran;Kime, Louise;McDowall, Kenneth J.
  • 通讯作者:
    McDowall, Kenneth J.
Direct entry by RNase E is a major pathway for the degradation and processing of RNA in Escherichia coli.
  • DOI:
    10.1093/nar/gku808
  • 发表时间:
    2014-10
  • 期刊:
  • 影响因子:
    14.9
  • 作者:
    Clarke JE;Kime L;Romero A D;McDowall KJ
  • 通讯作者:
    McDowall KJ
Adjacent single-stranded regions mediate processing of tRNA precursors by RNase E direct entry.
相邻的单链区域通过RNase E直接进入介导TRNA前体的处理。
  • DOI:
    10.1093/nar/gkt1403
  • 发表时间:
    2014-04
  • 期刊:
  • 影响因子:
    14.9
  • 作者:
    Kime L;Clarke JE;Romero A D;Grasby JA;McDowall KJ
  • 通讯作者:
    McDowall KJ
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Kenneth McDowall其他文献

Kenneth McDowall的其他文献

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{{ truncateString('Kenneth McDowall', 18)}}的其他基金

Mechanisms of RNA processing and decay that are dependent on RNaseE and related enzymes
依赖于 RNaseE 和相关酶的 RNA 加工和降解机制
  • 批准号:
    BB/D016096/1
  • 财政年份:
    2006
  • 资助金额:
    $ 44.93万
  • 项目类别:
    Research Grant

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