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Functional analysis of the TTF complex and its role in neurodevelopmental diseases

TTF复合物的功能分析及其在神经发育疾病中的作用

基本信息

批准号：
271023333
负责人：
Professor Dr. Utz Fischer
金额：
--
依托单位：
Lehrstuhl für Biochemie I
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2015
资助国家：
德国
起止时间：
2014-12-31 至 2018-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/271023333?language=en
关键词：
Functional analysis TTF complex its

项目摘要

Topoisomerases are enzymes believed to act predominantly, if not exclusively, on DNA substrates in cells of all kingdoms. It was therefore a surprise when two labs, including ours, provided evidence that eukaryotic topoisomerase TOP3ß is a cytosolic RNA binding protein that exhibits enzymatic activity on RNA substrates in vitro. Our biochemical studies have further shown that TOP3ß forms together with TDRD3, a scaffolding protein, and FMRP, affected in Fragile X mental retardation syndrome (FXS), an as yet unknown trimeric complex in vivo. This unit, which we have named TOP3ß-TDRD3-FMRP (TTF) complex, is recruited to mRNPs via the exon junction complex (EJC) in a sequence independent manner. The biochemical composition of TTF-containing mRNPs and their association with polysomes further suggests that they are engaged in the pioneer round of translation. However, neither the in vivo RNA targets of the TTF complex nor its regulatory mode of action on RNA are known. Interestingly, deletion of the TOP3ß-gene is associated with schizophrenia and intellectual disability. It is therefore possible that the etiologies of schizophrenia and FXS intersect at the post-transcriptional regulation of RNA molecules associated with TOP3ß and FMRP. This project aims to elucidate the role of TTF in RNA metabolism by a) identifying the RNA targets of the TTF complex in vivo and b) determining its catalytic and/or regulatory function in RNA metabolism. These studies will also help to c) shed light on a potential RNA-based etiology of neuropsychiatric disorders.

拓扑异构酶被认为是在所有王国的细胞中主要作用于DNA底物的酶。因此，当包括我们在内的两个实验室提供证据表明真核拓扑异构酶TOP3ß是一种胞质RNA结合蛋白，在体外对RNA底物表现出酶活性时，我们感到惊讶。我们的生化研究进一步表明，TOP3ß与TDRD3（一种支架蛋白）和FMRP一起形成，影响脆性X智力迟钝综合征（FXS），这是一种体内未知的三聚体复合物。我们将其命名为TOP3ß-TDRD3-FMRP （TTF）复合体，它通过外显子连接复合体（EJC）以序列独立的方式招募到mrnp中。含有ttf的mRNPs的生化组成及其与多聚体的关联进一步表明，它们参与了翻译的先驱回合。然而，TTF复合物的体内RNA靶点及其对RNA的调节模式都不为人所知。有趣的是，top3 ß-基因的缺失与精神分裂症和智力残疾有关。因此，精神分裂症和FXS的病因可能在与TOP3ß和FMRP相关的RNA分子的转录后调控上交叉。本项目旨在通过a)在体内鉴定TTF复合物的RNA靶点和b)确定其在RNA代谢中的催化和/或调节功能来阐明TTF在RNA代谢中的作用。这些研究也将有助于阐明神经精神疾病潜在的基于rna的病因学。