Substrate targeting by the Gcn5 acetyltransferase: mechanisms and consequences
Gcn5 乙酰转移酶的底物靶向:机制和后果
基本信息
- 批准号:RGPIN-2016-05015
- 负责人:
- 金额:$ 2.62万
- 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:2020
- 资助国家:加拿大
- 起止时间:2020-01-01 至 2021-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Problem: Acetylation of lysine residues is catalyzed by histone acetyltransferases (HATs) and removed by histone deacetylases (HDACs). As reflected by their names, these enzymes are best characterized as modifiers of histones. Yet, recent work from our lab and others suggests the need for a paradigm shift in how we think about acetylation as a post-translational modification. Specifically, acetylation is now thought to rival phosphorylation, with 1000s of substrates having been identified in organisms from bacteria to humans. How these substrates are chosen and what their acetylations do is not understood. Our overarching goal is to advance knowledge by determining the regulation and consequences of acetylation on a proteome-wide scale. To achieve this goal, it is necessary for us to move away from old models for acetylation based on the now-outdated assumption that histones are the only important targets.
Recent Progress: HAT and HDAC enzymes exist in large protein complexes with many subunits. Our data in yeast show that these complexes hold the key to understanding HATs and HDACs as global regulators. We focused on a complex called SAGA that contains an important HAT called Gcn5. Non-catalytic components of SAGA are usually assumed to be uniform and obligate promoters of acetylation by this HAT. Our data show that while this is true for histones, the impact of non-catalytic subunits on the acetylation of other proteins is target specific. Based on these data, we propose a new model wherein SAGA acts as a substrate selection platform. In this model, individual subunits promote or inhibit the acetylation of distinct sets of non-histone targets mediating diverse functions in the cell.
Approach and Significance: In this program, we will exploit our new model for the SAGA HAT complex to uncover mechanisms of substrate targeting and to link substrate acetylation to downstream functions. In the short term, trainees in my lab will use proteomics and functional genomics technologies in yeast to achieve three objectives. They will: (1) Determine how each subunit of SAGA impacts acetylation of Gcn5 targets; (2) identify novel genetic interactions for SAGA mutants; and (3) elucidate the function of SAGA-regulated acetylations on non-histone substrates. In the long term, we will extend what we learn from these experiments to the study of other HAT and HDAC complexes and determine how mechanisms of substrate targeting are impacted by changes to a cell's environment. Our program will facilitate research by other labs around the world by providing the first comprehensive picture of acetylation targeting and function to date.
Training: This program will train at least 2 graduate students and up to 10 undergrads over the next 5 years. They will gain experience in proteomics, high-throughput genetics and bioinformatics. These skills will make them highly qualified for positions in both academia and industry.
问题:赖氨酸残基的乙酰化由组蛋白乙酰转移酶(HATs)催化,并由组蛋白去乙酰化酶(HDACs)去除。正如它们的名字所反映的那样,这些酶最好的特点是作为组蛋白的修饰剂。然而,我们的实验室和其他人最近的工作表明,我们需要改变对乙酰化作为翻译后修饰的看法。具体地说,乙酰化现在被认为是与磷酸化相竞争的,从细菌到人类的生物体中已经发现了数千种底物。这些底物是如何被选择的以及它们的乙酰化作用是什么还不清楚。我们的首要目标是通过在蛋白质组范围内确定乙酰化的调节和后果来推进知识。为了实现这一目标,我们有必要放弃基于现在已经过时的假设——组蛋白是唯一重要的靶标——的旧的乙酰化模型。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Downey, Michael其他文献
Atomic structure of the KEOPS complex: an ancient protein kinase-containing molecular machine.
- DOI:
10.1016/j.molcel.2008.10.002 - 发表时间:
2008-10-24 - 期刊:
- 影响因子:16
- 作者:
Mao, Daniel Y. L.;Neculai, Dante;Downey, Michael;Orlicky, Stephen;Haffani, Yosr Z.;Ceccarelli, Derek F.;Ho, Jenny S. L.;Szilard, Rachel K.;Zhang, Wei;Ho, Cynthia S.;Wan, Leo;Fares, Christophe;Rumpel, Sigrun;Kurinov, Igor;Arrowsmith, Cheryl H.;Durocher, Daniel;Sicheri, Frank - 通讯作者:
Sicheri, Frank
The promises of lysine polyphosphorylation as a regulatory modification in mammals are tempered by conceptual and technical challenges
- DOI:
10.1002/bies.202100058 - 发表时间:
2021-05-16 - 期刊:
- 影响因子:4
- 作者:
Baijal, Kanchi;Downey, Michael - 通讯作者:
Downey, Michael
A Broad Response to Intracellular Long-Chain Polyphosphate in Human Cells
- DOI:
10.1016/j.celrep.2020.108318 - 发表时间:
2020-10-27 - 期刊:
- 影响因子:8.8
- 作者:
Bondy-Chorney, Emma;Abramchuk, Iryna;Downey, Michael - 通讯作者:
Downey, Michael
Gcn5 and sirtuins regulate acetylation of the ribosomal protein transcription factor Ifh1.
- DOI:
10.1016/j.cub.2013.06.050 - 发表时间:
2013-09-09 - 期刊:
- 影响因子:9.2
- 作者:
Downey, Michael;Knight, Britta;Vashisht, Ajay A.;Seller, Charles A.;Wohlschlegel, James A.;Shore, David;Toczyski, David P. - 通讯作者:
Toczyski, David P.
Acetylome Profiling Reveals Overlap in the Regulation of Diverse Processes by Sirtuins, Gcn5, and Esa1
- DOI:
10.1074/mcp.m114.043141 - 发表时间:
2015-01-01 - 期刊:
- 影响因子:7
- 作者:
Downey, Michael;Johnson, Jeffrey R.;Toczyski, David P. - 通讯作者:
Toczyski, David P.
Downey, Michael的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Downey, Michael', 18)}}的其他基金
Molecular control of non-histone protein acetylation in budding yeast
芽殖酵母非组蛋白乙酰化的分子控制
- 批准号:
RGPAS-2021-00003 - 财政年份:2022
- 资助金额:
$ 2.62万 - 项目类别:
Discovery Grants Program - Accelerator Supplements
Molecular control of non-histone protein acetylation in budding yeast
芽殖酵母非组蛋白乙酰化的分子控制
- 批准号:
RGPIN-2021-03887 - 财政年份:2022
- 资助金额:
$ 2.62万 - 项目类别:
Discovery Grants Program - Individual
Molecular control of non-histone protein acetylation in budding yeast
芽殖酵母非组蛋白乙酰化的分子控制
- 批准号:
RGPIN-2021-03887 - 财政年份:2021
- 资助金额:
$ 2.62万 - 项目类别:
Discovery Grants Program - Individual
Molecular control of non-histone protein acetylation in budding yeast
芽殖酵母非组蛋白乙酰化的分子控制
- 批准号:
RGPAS-2021-00003 - 财政年份:2021
- 资助金额:
$ 2.62万 - 项目类别:
Discovery Grants Program - Accelerator Supplements
Substrate targeting by the Gcn5 acetyltransferase: mechanisms and consequences
Gcn5 乙酰转移酶的底物靶向:机制和后果
- 批准号:
RGPIN-2016-05015 - 财政年份:2019
- 资助金额:
$ 2.62万 - 项目类别:
Discovery Grants Program - Individual
Substrate targeting by the Gcn5 acetyltransferase: mechanisms and consequences
Gcn5 乙酰转移酶的底物靶向:机制和后果
- 批准号:
RGPIN-2016-05015 - 财政年份:2018
- 资助金额:
$ 2.62万 - 项目类别:
Discovery Grants Program - Individual
Substrate targeting by the Gcn5 acetyltransferase: mechanisms and consequences
Gcn5 乙酰转移酶的底物靶向:机制和后果
- 批准号:
RGPIN-2016-05015 - 财政年份:2017
- 资助金额:
$ 2.62万 - 项目类别:
Discovery Grants Program - Individual
Substrate targeting by the Gcn5 acetyltransferase: mechanisms and consequences
Gcn5 乙酰转移酶的底物靶向:机制和后果
- 批准号:
RGPIN-2016-05015 - 财政年份:2016
- 资助金额:
$ 2.62万 - 项目类别:
Discovery Grants Program - Individual
相似国自然基金
靶向PARylation介导的DNA损伤修复途径在恶性肿瘤治疗中的作用与分子机制研究
- 批准号:82373145
- 批准年份:2023
- 资助金额:49.00 万元
- 项目类别:面上项目
诱导性多能干细胞rDNA区基因打靶在线粒体视神经病中的治疗研究
- 批准号:81970829
- 批准年份:2019
- 资助金额:55.0 万元
- 项目类别:面上项目
Pre-targeting/Click反应介导的自体循环干细胞在心脏缺血损伤修复中的应用及机制研究
- 批准号:81873493
- 批准年份:2018
- 资助金额:57.0 万元
- 项目类别:面上项目
以IGF2/IGF1R与SYT/SSX1为靶点治疗滑膜肉瘤的实验研究
- 批准号:81102033
- 批准年份:2011
- 资助金额:20.0 万元
- 项目类别:青年科学基金项目
基于ZFN/phiC31系统的新型基因打靶技术的建立(果蝇)
- 批准号:31171278
- 批准年份:2011
- 资助金额:60.0 万元
- 项目类别:面上项目
APO-miR(multi-targeting apoptosis-regulatory miRNA)在前列腺癌中的表达和作用
- 批准号:81101529
- 批准年份:2011
- 资助金额:22.0 万元
- 项目类别:青年科学基金项目
相似海外基金
Substrate targeting by the Gcn5 acetyltransferase: mechanisms and consequences
Gcn5 乙酰转移酶的底物靶向:机制和后果
- 批准号:
RGPIN-2016-05015 - 财政年份:2019
- 资助金额:
$ 2.62万 - 项目类别:
Discovery Grants Program - Individual
Substrate targeting by the Gcn5 acetyltransferase: mechanisms and consequences
Gcn5 乙酰转移酶的底物靶向:机制和后果
- 批准号:
RGPIN-2016-05015 - 财政年份:2018
- 资助金额:
$ 2.62万 - 项目类别:
Discovery Grants Program - Individual
Substrate targeting by the Gcn5 acetyltransferase: mechanisms and consequences
Gcn5 乙酰转移酶的底物靶向:机制和后果
- 批准号:
RGPIN-2016-05015 - 财政年份:2017
- 资助金额:
$ 2.62万 - 项目类别:
Discovery Grants Program - Individual
Substrate targeting by the Gcn5 acetyltransferase: mechanisms and consequences
Gcn5 乙酰转移酶的底物靶向:机制和后果
- 批准号:
RGPIN-2016-05015 - 财政年份:2016
- 资助金额:
$ 2.62万 - 项目类别:
Discovery Grants Program - Individual
GCN5-mediated transcription in AIDS pathogen Toxoplasma
艾滋病病原体弓形虫中 GCN5 介导的转录
- 批准号:
7806539 - 财政年份:2009
- 资助金额:
$ 2.62万 - 项目类别:
GCN5-mediated transcription in AIDS pathogen Toxoplasma
艾滋病病原体弓形虫中 GCN5 介导的转录
- 批准号:
7620186 - 财政年份:2009
- 资助金额:
$ 2.62万 - 项目类别:
GCN5-mediated transcription in AIDS pathogen Toxoplasma
艾滋病病原体弓形虫中 GCN5 介导的转录
- 批准号:
8060549 - 财政年份:2009
- 资助金额:
$ 2.62万 - 项目类别:
GCN5-mediated transcription in AIDS pathogen Toxoplasma
艾滋病病原体弓形虫中 GCN5 介导的转录
- 批准号:
8452684 - 财政年份:2009
- 资助金额:
$ 2.62万 - 项目类别:
GCN5-mediated transcription in AIDS pathogen Toxoplasma
艾滋病病原体弓形虫中 GCN5 介导的转录
- 批准号:
8260409 - 财政年份:2009
- 资助金额:
$ 2.62万 - 项目类别:
Mechanisms for all-inclusive controls of cell cycle progression, and IgM H and L-chain gene expressions by GCN5 and HDAC2
GCN5 和 HDAC2 全面控制细胞周期进程以及 IgM H 和 L 链基因表达的机制
- 批准号:
16310134 - 财政年份:2004
- 资助金额:
$ 2.62万 - 项目类别:
Grant-in-Aid for Scientific Research (B)