Ribosome stalling and activation of stress responses
核糖体停滞和应激反应激活
基本信息
- 批准号:10296101
- 负责人:
- 金额:$ 32.45万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-07-27 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAgreementAlkylationBindingBiochemistryCell DeathCellsChemicalsComplexCryoelectron MicroscopyCuesDNA DamageDNA RepairDNA Repair PathwayDataDefectEnsureEukaryotaEventFailureFrequenciesFundingGene ExpressionGenetic TranscriptionKineticsLinkMammalsMessenger RNAMolecularMolecular ConformationMutationNuclearNucleic AcidsOrganismOutputPathway interactionsPeptide Initiation FactorsPhosphorylationPhosphotransferasesPlayPost-Transcriptional RegulationPost-Translational Protein ProcessingProcessProductionProtein BiosynthesisProtein KinaseProteinsQuality ControlRNARecoveryRegulationResortResourcesRibosomal ProteinsRibosomesRoleSaccharomyces cerevisiaeSentinelSignal TransductionSiteStressStructureStudy modelsTATA-Box Binding ProteinTestingTherapeuticThermodynamicsTimeTranscription CoactivatorTranscriptional RegulationTranslationsUbiquitinationYeastsbiological adaptation to stresscancer cellexperimental studyinsightoxidationreconstitutionrecruitresponsesensortranscription factortranscriptional reprogrammingubiquitin-protein ligaseyeast genetics
项目摘要
PROJECT SUMMARY/ABSTRACT
During protein synthesis, the ribosome integrates multiple cues to ensure that the correct protein is made at the
right place, the right time and at the right concentration. These cues are the result of signals triggered by varying
cellular needs and environmental conditions such as proliferation and stress. In eukaryotes, the integrated-stress
response (ISR) responds to stresses through the activation of kinases that act on the initiation factor eIF2.
Phosphorylation of eIF2 represses global translation, but also derepresses translation of key pro-survival
mRNAs. In yeast, ISR is activated by the eIF2 kinase Gcn2. Recent studies from several groups, including
ours, have pointed to a central role for ribosomes and in particular their stalling during the activation of ISR.
Interestingly, ribosome stalling also activates ribosome-quality control (RQC), which depends critically on an E3
ligase Hel2. During the previous funding period, we established that Hel2 is activated in response to ribosome
collisions and showed that chemical insults that damage RNA trigger RQC. Notably, these very same agents
also activate ISR, suggesting that RQC and ISR are tightly be coordinated. In a very recent study, we showed
that not only do ribosome collisions activate both processes, but that the activation of one suppresses that of the
other. Emerging from these studies is the observation that collided ribosomes are widely used as sensors to
trigger an appropriate response, depending on the type and level of stress. Indeed, in preliminary data presented
in this proposal, we provide compelling evidence for a role for ribosome collisions in signaling to other nucleic
acid damage pathways, particular those involved in DNA-damage repair. This proposal is focused on
understanding the molecular rationale by which collided ribosomes can activate these seemingly unrelated
processes. Our preliminary data indicate that the A status of the ribosome is important for ISR activation, and in
Aim 1 we will probe the conformation of ribosomes under various stress conditions and assess how they impact
Gcn2 recruitment. We will expand on these studies by reconstituting ISR and RQC activities to provide a
mechanistic understanding for the apparent preferential activation of RQC over ISR. Notably, robust ISR also
requires the presence of the highly conserved transcriptional coactivator Mbf1, which we and others showed to
bind collided ribosomes. In Aim 2, we will test the hypothesis that stalling activates ISR using a two-pronged
mechanism, in which collided ribosomes in addition to activating Gcn2 modulate ISR coactivation by Mbf1. In
particular, we will dissect the role of Mbf1 interactions with the ribosome in regulating its function through post-
translational modification. Finally, we have a wealth of preliminary data linking RNA-quality control processes
with DNA repair. Aim 3 establishing molecular details about how signaling is transduced between the two
processes, which is hitherto unexplored. Altogether, we will leverage our expertise in ribosome biochemistry and
yeast genetics in combination with resources we accrued over the past funding period to reveal how collided
ribosomes provide a structural platform for several conserved signaling processes.
项目总结/摘要
在蛋白质合成过程中,核糖体整合了多种信号,以确保正确的蛋白质是在蛋白质合成过程中产生的。
在正确的时间,正确的地点,正确的浓度这些线索是由不同的信号触发的结果
细胞需要和环境条件,如增殖和压力。在真核生物中,
应激反应(ISR)通过激活作用于起始因子eIF 2 β的激酶来应答应激。
eIF 2 β的磷酸化抑制了整体翻译,但也解除了关键促生存因子的翻译。
mRNA。在酵母中,ISR被eIF 2 β激酶Gcn 2激活。几个团体最近的研究,包括
我们的研究已经指出了核糖体的核心作用,特别是它们在ISR激活过程中的停滞。
有趣的是,核糖体停滞也激活核糖体质量控制(RQC),这主要取决于E3
连接酶Hel 2。在上一个资助期间,我们确定了Hel 2是响应于核糖体激活的。
碰撞,并表明化学损伤,破坏RNA触发RQC。值得注意的是,这些特工
并激活ISR,表明RQC和ISR紧密协调。在最近的一项研究中,
不仅核糖体碰撞激活了这两个过程,而且其中一个过程的激活抑制了另一个过程的激活。
其他.从这些研究中发现,碰撞的核糖体被广泛用作传感器,
根据压力的类型和程度,触发适当的反应。事实上,在初步数据中,
在这个提议中,我们提供了令人信服证据,证明核糖体碰撞在向其他核
酸损伤途径,特别是参与DNA损伤修复的途径。该提案的重点是
了解碰撞的核糖体可以激活这些看似无关的分子原理
流程.我们的初步数据表明,核糖体的A状态对ISR激活很重要,
目标1我们将探测各种应激条件下核糖体的构象并评估它们的影响
GCN 2招聘我们将通过重组ISR和RQC活动来扩展这些研究,
对RQC比ISR明显优先活化的机理理解。值得注意的是,强大的ISR还
需要高度保守的转录辅激活因子Mbf 1的存在,我们和其他人表明,
结合碰撞的核糖体。在目标2中,我们将使用一个双管齐下的方法来测试失速激活ISR的假设。
机制,其中碰撞的核糖体除了激活Gcn 2调节ISR共激活Mbf 1。在
特别是,我们将剖析Mbf 1与核糖体相互作用的作用,通过后
翻译修饰最后,我们有丰富的初步数据连接RNA质量控制过程
DNA修复。目的3建立关于两者之间信号转导的分子细节
过程,这是迄今为止尚未探索的。总之,我们将利用我们在核糖体生物化学方面的专业知识,
酵母遗传学结合我们在过去的资助期间积累的资源,以揭示如何碰撞
核糖体为几种保守的信号传导过程提供了结构平台。
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 }}
Hani Zaher其他文献
Hani Zaher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('Hani Zaher', 18)}}的其他基金
Reading frame maintenance by the ribosome during stalling
停顿期间核糖体的阅读框维护
- 批准号:
10181827 - 财政年份:2021
- 资助金额:
$ 32.45万 - 项目类别:
Reading frame maintenance by the ribosome during stalling
停顿期间核糖体的阅读框维护
- 批准号:
10398184 - 财政年份:2021
- 资助金额:
$ 32.45万 - 项目类别:
Reading frame maintenance by the ribosome during stalling
停顿期间核糖体的阅读框维护
- 批准号:
10596204 - 财政年份:2021
- 资助金额:
$ 32.45万 - 项目类别:
Ribosome stalling and activation of stress responses
核糖体停滞和应激反应激活
- 批准号:
10801772 - 财政年份:2015
- 资助金额:
$ 32.45万 - 项目类别:
Ribosome stalling and activation of stress responses
核糖体停滞和应激反应激活
- 批准号:
10653178 - 财政年份:2015
- 资助金额:
$ 32.45万 - 项目类别:
THE ROLE OF THE RIBOSOME IN DETERMINING THE FATE OF DAMAGED MRNA
核糖体在决定受损 mRNA 命运中的作用
- 批准号:
10389131 - 财政年份:2015
- 资助金额:
$ 32.45万 - 项目类别:
THE ROLE OF THE RIBOSOME IN DETERMINING THE FATE OF DAMAGED MRNA
核糖体在决定受损 mRNA 命运中的作用
- 批准号:
9115638 - 财政年份:2015
- 资助金额:
$ 32.45万 - 项目类别:
Ribosome stalling and activation of stress responses
核糖体停滞和应激反应激活
- 批准号:
10442575 - 财政年份:2015
- 资助金额:
$ 32.45万 - 项目类别:
The molecular mechanism of post-peptidyl quality control on the ribosome
核糖体肽基后质量控制的分子机制
- 批准号:
8135525 - 财政年份:2010
- 资助金额:
$ 32.45万 - 项目类别:
The molecular mechanism of post-peptidyl quality control on the ribosome
核糖体肽基后质量控制的分子机制
- 批准号:
8725512 - 财政年份:2010
- 资助金额:
$ 32.45万 - 项目类别:
相似海外基金
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 32.45万 - 项目类别:
Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 32.45万 - 项目类别:
Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 32.45万 - 项目类别:
Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 32.45万 - 项目类别:
Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 32.45万 - 项目类别:
Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 32.45万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 32.45万 - 项目类别:
Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
- 批准号:
2301846 - 财政年份:2023
- 资助金额:
$ 32.45万 - 项目类别:
Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 32.45万 - 项目类别:
Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
- 批准号:
23K16076 - 财政年份:2023
- 资助金额:
$ 32.45万 - 项目类别:
Grant-in-Aid for Early-Career Scientists