Investigation into the role of Secisbp2 in re-coding of UGA codons in selenoproteins by global ribosomal footprinting

通过全局核糖体足迹研究 Secisbp2 在硒蛋白中 UGA 密码子重新编码中的作用

基本信息

项目摘要

Selenoproteins are essential for mammals. They contain the rare amino acid selenocysteine (Sec). Sec is the first known natural expansion of the genetic code. Incorporation of Sec in proteins requires the re-coding of a UGA (stop) codon. For re-coding, selenoprotein mRNAs contain the selenocysteine insertion sequence (SECIS) element in the 3(prime)-untranslated region. Mutations in SECIS-binding protein 2 (SECISBP2) in human lead to congenital defects of selenoprotein biosynthesis entailing neurological, endocrinological, and immunological symptoms. In the first funding period, we have generated and studied mouse models with mutations in Secisbp2. We have found that Secisbp2 does not only stimulate UGA re-coding, but carries an unexpected function by stabilizing selenoprotein mRNAs. In the next funding period, we will analyze selenoprotein biosynthesis on a global scale in unusual detail by using Ribosomal Profiling. We will follow four aims: (1) Determine the re-coding efficiency at UGA codons in the presence of not of Secisbp2. Using our novel mouse models, we will determine the influence of Secisbp2 on translation of UGA as Sec. (2) Do point mutations in Secisbp2 (targeting the SID-domain or L7Ae domain) alter the re-coding efficiency at UGA? This approach will allow us to understand how pathogenic point mutations affect Secisbp2 functions. (3) STOP does not equal STOP: What is the difference between stalling ribosomes lacking Secisbp2 or tRNA(Sec), respectively, with respect to UGA re-coding and mRNA surveillance pathways like Nonsense-Mediated Decay and No-Go Decay? (4) What is the exact mechanism of mRNA degradation, if Secisbp2 or tRNA(Sec) is lacking? This question will be approached by genetic manipulation in a hepatocyte cell model. We expect to gain fundamental insights into current questions of translation of non-canonical amino acids as well as into the normal role of No-Go Decay in mammals.
硒蛋白是哺乳动物所必需的。它们含有罕见的氨基酸硒代半胱氨酸(Sec)。Sec是第一个已知的遗传密码的自然扩展。Sec在蛋白质中的掺入需要UGA(终止)密码子的重新编码。为了重新编码,硒蛋白mRNA在3(prime)-非翻译区中含有硒代半胱氨酸插入序列(SECIS)元件。SECIS结合蛋白2(SECISBP 2)的突变导致人类硒蛋白生物合成的先天性缺陷,从而引起神经、内分泌和免疫症状。在第一个资助期内,我们已经生成并研究了Secisbp 2突变的小鼠模型。我们已经发现Secisbp 2不仅刺激UGA重新编码,而且通过稳定硒蛋白mRNA而具有意想不到的功能。在下一个资助期内,我们将通过使用核糖体分析在全球范围内分析硒蛋白的生物合成。我们将遵循四个目标:(1)确定在Secisbp 2不存在的情况下UGA密码子的重编码效率。使用我们的新型小鼠模型,我们将确定Secisbp 2对UGA翻译为Sec的影响。(2)Secisbp 2的点突变(靶向SID结构域或L7 Ae结构域)是否会改变UGA的重编码效率?这种方法将使我们能够了解致病性点突变如何影响Secisbp 2功能。(3)STOP不等于STOP:分别缺乏Secisbp 2或tRNA(Sec)的停滞核糖体在UGA重编码和mRNA监视途径(如无义介导的衰变和No-Go衰变)方面有什么区别?(4)如果缺乏Secisbp 2或tRNA(Sec),mRNA降解的确切机制是什么?这个问题将通过在肝细胞模型中进行遗传操作来解决。我们期望获得对当前非经典氨基酸翻译问题以及No-Go Decay在哺乳动物中的正常作用的基本见解。

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Ribosome profiling of selenoproteins in vivo reveals consequences of pathogenic Secisbp2 missense mutations
  • DOI:
    10.1074/jbc.ra119.009369
  • 发表时间:
    2019-07
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Wenchao Zhao;Simon Bohleber;Henrik Schmidt;Sandra Seeher;M. Howard;Doreen Braun;S. Arndt;Uschi Reuter;H. Wende;C. Birchmeier;Noelia Fradejas-Villar;U. Schweizer
  • 通讯作者:
    Wenchao Zhao;Simon Bohleber;Henrik Schmidt;Sandra Seeher;M. Howard;Doreen Braun;S. Arndt;Uschi Reuter;H. Wende;C. Birchmeier;Noelia Fradejas-Villar;U. Schweizer
Homozygous mutation in TXNRD1 is associated with genetic generalized epilepsy
  • DOI:
    10.1016/j.freeradbiomed.2017.02.040
  • 发表时间:
    2017-05-01
  • 期刊:
  • 影响因子:
    7.4
  • 作者:
    Kudin, Alexei P.;Baron, Gregor;Kunz, Wolfram S.
  • 通讯作者:
    Kunz, Wolfram S.
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Professor Dr. Ulrich Schweizer其他文献

Professor Dr. Ulrich Schweizer的其他文献

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{{ truncateString('Professor Dr. Ulrich Schweizer', 18)}}的其他基金

The effect on translational efficiency of the i6A37 modification in cytoplasmic and mitochondrial tRNAs: Mitochondrial and selenoproteins.
细胞质和线粒体 tRNA 中 i6A37 修饰对翻译效率的影响:线粒体和硒蛋白。
  • 批准号:
    277195918
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:
    Priority Programmes
Biochemical and structural characterization of mammalian deiodinases as key regulators of thyroid hormone metabolism
哺乳动物脱碘酶作为甲状腺激素代谢关键调节剂的生化和结构特征
  • 批准号:
    280029505
  • 财政年份:
    2015
  • 资助金额:
    --
  • 项目类别:
    Priority Programmes
Structure and function of the thyroid hormone transporter MCT8
甲状腺激素转运蛋白MCT8的结构和功能
  • 批准号:
    221029121
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
    Priority Programmes

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