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Novel functions of alternative pre-mRNA splicing coupled with nonsense-mediated decay

选择性前 mRNA 剪接与无义介导的衰变相结合的新功能

基本信息

批准号：
BB/M007103/1
负责人：
Eugene Makeyev
金额：
$ 45.32万
依托单位：
King's College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2015
资助国家：
英国
起止时间：
2015 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=BB%2FM007103%2F1
关键词：
Novel functions alternative pre mRNA

项目摘要

Precise regulation of cell- and tissue-specific genes is indispensable for proper development and function of our organism. Importantly, abnormal gene expression has been linked to devastating neurological and neuropsychiatric diseases such as myotonic dystrophy, spinal muscular atrophy, amyotrophic lateral sclerosis, Alzheimer's disease and dementias. Yet another example of potentially dire consequences caused by defective genes is provided by a range of hereditary disorders affecting multiple tissues and organs. Many of these conditions are associated with considerable patient suffering and mortality and constitute a serious burden for the national health system.Expression of our genes proceeds as a succession of distinct molecular steps that include transcription, processing of primary transcripts into messengers, and ultimately translation of the messengers into proteins. Several control mechanisms operating at each of these steps ensure that protein products of our genes appear in the right place and at the right time. One such control called nonsense-mediated decay, or NMD, eliminates messengers with defective protein-coding capacity thus allowing the cell to cope with deleterious mutations and occasional errors in primary transcript processing. Surprisingly, recent studies suggest that this mechanism is also used to regulate gene expression under normal circumstances. In this case, corresponding primary transcripts can be processed to generate two or more alternative messenger variants, with some variants encoding proteins and the others degraded by NMD. Several genes indispensible for our nerve cells appear to be regulated in this manner and additional research in this field promises further exciting discoveries.Here we propose to uncover novel genes that are controlled by alternative processing/NMD during brain development and to begin understanding their functional significance. We will advance our research by combining molecular, cellular and developmental biology techniques with advanced bioinformatics approaches. Our work will have important biomedical implications. Indeed, at least one novel gene, Hps1, identified in our preliminary experiments has been directly linked to a hereditary disease called Hermansky-Pudlak Syndrome and understanding regulation of this gene will likely provide important insights into this and a large group of other metabolic disorders associated with similar molecular defects. Wider medical relevance of our study will be guaranteed by its general relevance to neurological and neuropsychiatric diseases associated with aberrant regulation of genes.

细胞和组织特异性基因的精确调控对于我们生物体的正常发育和功能是必不可少的。重要的是，异常基因表达与破坏性神经和神经精神疾病有关，如强直性肌营养不良、脊髓性肌萎缩、肌萎缩性侧索硬化、阿尔茨海默病和痴呆。另一个由缺陷基因引起的潜在可怕后果的例子是影响多种组织和器官的一系列遗传性疾病。其中许多疾病与相当多的病人痛苦和死亡率有关，对国家卫生系统构成严重负担。我们基因的表达是一系列不同的分子步骤，包括转录，初级转录物加工成信使，最终将信使翻译成蛋白质。在这些步骤中的每一步都有几个控制机制，以确保我们基因的蛋白质产物在正确的时间和正确的地点出现。一种称为无义介导的衰变（NMD）的控制消除了具有缺陷蛋白质编码能力的信使，从而使细胞能够科普初级转录处理中的有害突变和偶尔的错误。令人惊讶的是，最近的研究表明，这种机制也用于调节正常情况下的基因表达。在这种情况下，可以加工相应的初级转录物以产生两种或更多种替代信使变体，其中一些变体编码蛋白质，而其他变体被NMD降解。我们的神经细胞不可或缺的几个基因似乎是以这种方式进行调节，在这一领域的其他研究有望进一步令人兴奋的发现。在这里，我们建议发现新的基因，在大脑发育过程中的替代处理/NMD控制，并开始了解其功能的意义。我们将通过结合分子，细胞和发育生物学技术与先进的生物信息学方法来推进我们的研究。我们的工作将具有重要的生物医学意义。事实上，在我们的初步实验中发现的至少一种新基因Hps 1与一种名为Hermansky-Pudlak综合征的遗传性疾病直接相关，了解该基因的调控可能会为这种疾病以及与类似分子缺陷相关的一大群其他代谢疾病提供重要见解。我们的研究与基因异常调节相关的神经和神经精神疾病的普遍相关性将保证我们的研究具有更广泛的医学相关性。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Functional Evolution in Orthologous Cell-encoded RNA-dependent RNA Polymerases.

DOI：
10.1074/jbc.m115.685933
发表时间：
2016-04-22
期刊：
The Journal of biological chemistry
影响因子：
0
作者：
Qian X;Hamid FM;El Sahili A;Darwis DA;Wong YH;Bhushan S;Makeyev EV;Lescar J
通讯作者：
Lescar J

Functional Annotation of Custom Transcriptomes.

自定义转录组的功能注释。

DOI：
10.1007/978-1-0716-2521-7_9
发表时间：
2022
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Hamid F
通讯作者：
Hamid F

Exaptive origins of regulated mRNA decay in eukaryotes.

DOI：
10.1002/bies.201600100
发表时间：
2016-09
期刊：
BIOESSAYS
影响因子：
4
作者：
Hamid, Fursham M.;Makeyev, Eugene V.
通讯作者：
Makeyev, Eugene V.

Protocol for auxin-inducible depletion of the RNA-binding protein PTBP1 in mouse embryonic stem cells.

DOI：
10.1016/j.xpro.2023.102644
发表时间：
2023-12-15
期刊：
STAR PROTOCOLS
影响因子：
0
作者：
Kainov, Yaroslav;Zhuravskaya, Anna;Makeyev, Eugene, V
通讯作者：
Makeyev, Eugene, V

An RRM-ZnF RNA recognition module targets RBM10 to exonic sequences to promote exon exclusion.

DOI：
10.1093/nar/gkx225
发表时间：
2017-06-20
期刊：
Nucleic acids research
影响因子：
14.9
作者：
Collins KM;Kainov YA;Christodolou E;Ray D;Morris Q;Hughes T;Taylor IA;Makeyev EV;Ramos A
通讯作者：
Ramos A