Determining the molecular mechanism and functional importance of Eri1-dependent histone mRNA degradation

确定 Eri1 依赖性组蛋白 mRNA 降解的分子机制和功能重要性

• 批准号: 152044868
• 负责人: Professor Dr. Vigo Heissmeyer
• 金额: --
• 依托单位: Forschungsbereich Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/152044868?language=en
• 关键词: Determining; molecular; mechanism; functional; importance

Eri1-deficiency in mice results in a number of phenotypes, most prominently growth retardation, postnatal death and male sterility. The Eri1 protein is a 3 exoribonuclease and has been demonstrated to degrade RNAi-duplexes or process 5.8S rRNA molecules. Furthermore, Eri1 was found to bind to histone mRNA stem-loops for which a functional explanation remained elusive. Our current data convincingly demonstrate that Eri1 is required for replication-dependent histone mRNA degradation. Previous studies suggest that Eri1 selects histone mRNA targets by sequence-specific binding through its SAP (SAF-A/B, Acinus and PIAS) domain. Contradictory to these results, in our investigation of 5.8S rRNA processing this domain was found to be dispensable. The proposed experiments will clarify the molecular mechanism of Eri1-dependent histone mRNA degradation. We will determine mutual binding requirements in the Eri1 protein and histone mRNA and evaluate how these molecular determinants allow coordinated degradation of histone mRNAs. In addition we will search for the activity that restricts Eri1-dependent histone mRNA degradation to the end of S-phase. Studying male sterility in Eri1 knockout mice will allow us to correlate deregulation of histone mRNAs with critical alterations during sperm cell development and link the molecular mechanism to pathological changes in the animal model.

Eri1缺乏会导致许多表型，最突出的是生长迟缓、出生后死亡和男性不育。Eri1蛋白是一种3外核糖核酸酶，已被证明能降解RNAi-双链或处理5.8S rRNA分子。此外，Eri1被发现与组蛋白mRNA茎环结合，对其功能解释仍然难以捉摸。我们目前的数据令人信服地证明，Eri1是复制依赖的组蛋白mRNA降解所必需的。先前的研究表明，Eri1通过其SAP(SAF-A/B、Acinus和PIAS)结构域通过序列特异性结合来选择组蛋白mRNA靶标。与这些结果相反，在我们对5.8S rRNA处理的研究中，发现这个结构域是可有可无的。拟议的实验将阐明依赖Eri1的组蛋白mRNA降解的分子机制。我们将确定Eri1蛋白和组蛋白mRNA的相互结合要求，并评估这些分子决定因素如何允许组蛋白mRNAs的协调降解。此外，我们还将寻找限制Eri1依赖的组蛋白mRNA降解的活性，直到S期结束。研究Eri1基因敲除小鼠的雄性不育性将使我们能够将组蛋白mRNAs的解除调控与精子细胞发育过程中的关键变化联系起来，并将其分子机制与动物模型中的病理变化联系起来。

项目成果

Induced miR‐99a expression represses Mtor cooperatively with miR‐150 to promote regulatory T‐cell differentiation

• DOI: 10.15252/embj.201489589
• 发表时间: 2015-05
• 期刊: The EMBO Journal
• 作者: Sebastian C Warth;Kai P Hoefig;Anian Hiekel;S. Schallenberg;K. Jovanovic;L. Klein;Karsten Kretschmer;K. Ansel;V. Heissmeyer

Eri1 degrades the stem-loop of oligouridylated histone mRNAs to induce replication-dependent decay

• DOI: 10.1038/nsmb.2450
• 发表时间: 2013-01-01
• 期刊: NATURE STRUCTURAL & MOLECULAR BIOLOGY
• 影响因子: 16.8
• 作者: Hoefig, Kai P.;Rath, Nicola;Heissmeyer, Vigo
• 通讯作者: Heissmeyer, Vigo