Nuclear activity of carnitine acetyltransferase
肉毒碱乙酰转移酶的核活性
基本信息
- 批准号:RGPIN-2018-06089
- 负责人:
- 金额:$ 2.4万
- 依托单位:
- 依托单位国家:加拿大
- 项目类别:Discovery Grants Program - Individual
- 财政年份:2019
- 资助国家:加拿大
- 起止时间:2019-01-01 至 2020-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Introduction:***Acetyl-CoA emerges as one important mediator of the nuclear-mitochondrial crosstalk and compelling evidence indicates that availability of this central metabolite is a key regulator of cell growth and proliferation through modulation of particular protein acetylation reactions, especially those at histones in chromatin. During the course of our investigation on the chromatin remodelling in spermatids, we observed a transient hyperacetylation of histones associated with their eviction from the chromatin. However, a systematic mass spectrometry analysis of histone-associated proteins yielded no potential histone acetyltransferase candidate at these steps. However, we observed a near complete nuclear displacement of the mitochondrial carnitine acetyltransferase (CrAT) normally found in the mitochondria or peroxysomes in both mouse and human. Carnitine acetyltransferase (CrAT), catalyzes the freely reversible conversion of acetyl-CoA to its membrane permeant carnitine ester, acetylcarnitine. RNA analyses from human germ cells revealed splicing variants, one of which included retention of a partial intron that introduces an early in-frame stop codon forcing transcription from a downstream ATG and encoding a protein lacking the mitochondrial localisation signal that may have the potential for nuclear localisation owing for the presence of a degenerated nuclear localisation signal (NLS). Transfection experiments indicate that this variant can localize to the nucleus if the C-terminal peroxisomal targeting sequence (PTS) is hindered. The nuclear localization of CrAT may therefore modify the acetyl-CoA pool in this compartment allowing either enzymatic or non-enzymatic acetylation processes in the nucleus. In somatic cells, alteration of nuclear acetyl-CoA through the CrAT activity may have important consequences on genetic stability, mutagenesis and aging.***Hypothesis:***The nuclear addressing of CrAT impacts chromatin stability through acetylation of histones and other nuclear proteins.***Objectives:***Our goal is to investigate regulation of the nuclear addressing of CrAT and get the first insights into its biological role. Accordingly, the specific objectives for the next five years are:***1. To determine the consequence of CrAT nuclear expression on chromatin and acetylome***2. To determine the sequence and mechanism involved in CrAT nuclear addressing***3. To determine the impact of CrAT on genetic integrity and DNA damage response***Conclusion:***These experimental steps are part of our research program and will define the function of nuclear CrAT, in particular, whether it is involved in chromatin dynamics and genetic stability. Understanding the mitochondrial-nucleus crosstalk is key for rational intervention approaches in neurodegenerative disorders, aging and cancers. This will provide a stimulating research environment for the training of HQP.
前言:*乙酰辅酶A是核-线粒体串扰的重要介体之一,有力的证据表明,这种中心代谢物的可获得性是通过调节特定的蛋白质乙酰化反应,特别是染色质中的组蛋白反应,对细胞生长和增殖起关键调节作用。在我们研究精子细胞染色质重塑的过程中,我们观察到了与它们从染色质中驱逐出来相关的组蛋白的一过性超乙酰化。然而,对组蛋白相关蛋白的系统质谱分析在这些步骤中没有产生潜在的组蛋白乙酰转移酶候选者。然而,我们观察到线粒体肉碱乙酰转移酶(CrAT)几乎完全的核置换,该酶通常存在于小鼠和人类的线粒体或过氧化物酶中。肉碱乙酰转移酶(CrAT)催化乙酰辅酶A自由可逆地转化为其膜上的乙酰肉碱酯,即乙酰肉碱。对人类生殖细胞的RNA分析发现了剪接变体,其中之一包括保留了一个部分内含子,该内含子引入了一个早期的框内终止密码子,迫使从下游的ATG转录,并编码了一种缺乏线粒体定位信号的蛋白质,由于存在退化的核定位信号(NLS),该蛋白质可能具有核定位的可能性。转染实验表明,如果C末端的过氧化体靶向序列(PTS)受阻,该变异体可以定位于细胞核。因此,CrAT的核定位可能会改变该隔室中的乙酰辅酶A池,从而允许细胞核中的酶或非酶乙酰化过程。在体细胞中,通过CrAT活性改变核乙酰辅酶A可能对遗传稳定性、突变和衰老有重要影响。*假设:*CrAT的核寻址通过组蛋白和其他核蛋白的乙酰化影响染色质的稳定性。*目标:*我们的目标是研究CrAT的核寻址的调节,并初步了解其生物学作用。因此,未来五年的具体目标是:*1.确定CrAT核表达对染色质和乙酰体的影响*2.确定CrAT核寻址涉及的序列和机制*3.确定CrAT对遗传完整性和DNA损伤反应的影响*结论:*这些实验步骤是我们研究计划的一部分,将确定核CrAT的功能,特别是它是否参与染色质动力学和遗传稳定性。了解线粒体-细胞核串扰是合理干预神经退行性疾病、衰老和癌症的关键。这将为HQP的培训提供一个激励的研究环境。
项目成果
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Boissonneault, Guylain其他文献
Quantification and genome-wide mapping of DNA double-strand breaks
- DOI:
10.1016/j.dnarep.2016.10.005 - 发表时间:
2016-12-01 - 期刊:
- 影响因子:3.8
- 作者:
Gregoire, Marie-Chantal;Massonneau, Julien;Boissonneault, Guylain - 通讯作者:
Boissonneault, Guylain
DNA damage response during chromatin remodeling in elongating spermatids of mice
- DOI:
10.1095/biolreprod.107.064162 - 发表时间:
2008-02-01 - 期刊:
- 影响因子:3.6
- 作者:
Leduc, Fredric;Maquennehan, Vincent;Boissonneault, Guylain - 通讯作者:
Boissonneault, Guylain
Step-specific Sorting of Mouse Spermatids by Flow Cytometry
- DOI:
10.3791/53379 - 发表时间:
2015-12-01 - 期刊:
- 影响因子:1.2
- 作者:
Simard, Olivier;Leduc, Frederic;Boissonneault, Guylain - 通讯作者:
Boissonneault, Guylain
Spermiogenesis and DNA repair: A possible etiology of human infertility and genetic disorders
- DOI:
10.1080/19396360701876823 - 发表时间:
2008-01-01 - 期刊:
- 影响因子:2.4
- 作者:
Leduc, Frederic;Nkoma, Genevieve Bikond;Boissonneault, Guylain - 通讯作者:
Boissonneault, Guylain
Suboptimal extracellular pH values alter DNA damage response to induced double-strand breaks
- DOI:
10.1002/2211-5463.12384 - 发表时间:
2018-03-01 - 期刊:
- 影响因子:2.6
- 作者:
Massonneau, Julien;Ouellet, Camille;Boissonneault, Guylain - 通讯作者:
Boissonneault, Guylain
Boissonneault, Guylain的其他文献
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{{ truncateString('Boissonneault, Guylain', 18)}}的其他基金
Nuclear activity of carnitine acetyltransferase
肉毒碱乙酰转移酶的核活性
- 批准号:
RGPIN-2018-06089 - 财政年份:2022
- 资助金额:
$ 2.4万 - 项目类别:
Discovery Grants Program - Individual
Nuclear activity of carnitine acetyltransferase
肉毒碱乙酰转移酶的核活性
- 批准号:
RGPIN-2018-06089 - 财政年份:2021
- 资助金额:
$ 2.4万 - 项目类别:
Discovery Grants Program - Individual
Nuclear activity of carnitine acetyltransferase
肉毒碱乙酰转移酶的核活性
- 批准号:
RGPIN-2018-06089 - 财政年份:2020
- 资助金额:
$ 2.4万 - 项目类别:
Discovery Grants Program - Individual
Nuclear activity of carnitine acetyltransferase
肉毒碱乙酰转移酶的核活性
- 批准号:
RGPIN-2018-06089 - 财政年份:2018
- 资助金额:
$ 2.4万 - 项目类别:
Discovery Grants Program - Individual
Histone acetyltransferase and genetic integrity of the male gamete
组蛋白乙酰转移酶和雄配子的遗传完整性
- 批准号:
155182-2008 - 财政年份:2012
- 资助金额:
$ 2.4万 - 项目类别:
Discovery Grants Program - Individual
Direct determination of genetic integrity in bull semen
直接测定公牛精液中的遗传完整性
- 批准号:
428756-2011 - 财政年份:2011
- 资助金额:
$ 2.4万 - 项目类别:
Engage Grants Program
Histone acetyltransferase and genetic integrity of the male gamete
组蛋白乙酰转移酶和雄配子的遗传完整性
- 批准号:
155182-2008 - 财政年份:2011
- 资助金额:
$ 2.4万 - 项目类别:
Discovery Grants Program - Individual
Histone acetyltransferase and genetic integrity of the male gamete
组蛋白乙酰转移酶和雄配子的遗传完整性
- 批准号:
155182-2008 - 财政年份:2010
- 资助金额:
$ 2.4万 - 项目类别:
Discovery Grants Program - Individual
Histone acetyltransferase and genetic integrity of the male gamete
组蛋白乙酰转移酶和雄配子的遗传完整性
- 批准号:
155182-2008 - 财政年份:2009
- 资助金额:
$ 2.4万 - 项目类别:
Discovery Grants Program - Individual
Histone acetyltransferase and genetic integrity of the male gamete
组蛋白乙酰转移酶和雄配子的遗传完整性
- 批准号:
155182-2008 - 财政年份:2008
- 资助金额:
$ 2.4万 - 项目类别:
Discovery Grants Program - Individual
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肉毒碱乙酰转移酶的核活性
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