The novel role of microtubule regulators in the DNA damage response
微管调节剂在 DNA 损伤反应中的新作用
基本信息
- 批准号:10738331
- 负责人:
- 金额:$ 4.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-01 至 2025-12-31
- 项目状态:未结题
- 来源:
- 关键词:ATM activationATP HydrolysisAcetylationAutophagocytosisBindingBiochemicalBiologyCancer EtiologyCell Death InductionCell ProliferationCell SurvivalCellsChromatinChromatin Remodeling FactorChromatin StructureClinicalCommunicationComplexCytoplasmCytoplasmic StructuresCytoskeletonDNADNA DamageDNA Double Strand BreakDNA RepairDataDevelopmentDouble Strand Break RepairEnsureEtiologyEventExhibitsFamilyGenomeGenome StabilityGoalsHDAC1 geneHomeostasisHumanHypersensitivityIn VitroKinesinKinetochoresKnock-outKnowledgeLaboratoriesMaintenance TherapyMalignant NeoplasmsMediatingMicrotubule DepolymerizationMicrotubule StabilizationMicrotubulesMitoticModelingMotorMovementNonhomologous DNA End JoiningNuclearOrganellesPerceptionPhosphorylationPhysical condensationPlayPoisonProtein ArrayProteinsRadiationRegimenRegulationRelaxationRepairosome liposomeRoleSignal TransductionSiteTherapeuticToxic effectTubulinVesicleataxia telangiectasia mutated proteincancer therapychromatin remodelingcondensingenome integrityhistone methylationhuman diseaseimprovedin vivoinnovationinsightknock-downmembermutantnovelpharmacologicprotein complexprotein functionprotein transportrecruitrepairedresponsesegregationtherapy outcometooltumor progression
项目摘要
DNA damage, particularly DNA double strand break (DSB), has detrimental effects on cell survival and
genomic stability. In response to DNA damage, the cell activates several evolutionarily-conserved
mechanisms to repair DNA damage, halt cell proliferation, or induce cell death. These surveillance
mechanisms, collectively defined as the DNA damage response (DDR), constitute an important etiological
factor for many human diseases, especially cancer. Moreover, the DDR is a key determinant for the
therapeutic outcome of cancer treatment using radiation and other DNA damaging agents. A long-term
goal of our laboratory is to delineate new DDR factors and mechanisms using comprehensive
experimental tools, and thereby, revealing new insights into cancer progression and treatment. In a recent
effort to systematically identify new components of the DSB “repairosome”, we identified Kif2C and several
other MT regulators as potential DSB-associated proteins. Kif2C is rapidly recruited to DNA damage sites
and plays an essential role in DSB repair. Strikingly, Kif2C mediates the spatial movement of DSBs, and
controls DNA damage-induced chromatin remodeling. These functions of Kif2C are largely dependent on
its MT depolymerase activity, and are likely to be achieved via coordination with other MT regulators. On
the other hand, DNA damage modulates Kif2C phosphorylation and MT stabilization. These findings
suggest a novel inter-organelle crosstalk between MT components and the DDR machinery that differs
from the conventional perception that MT functions exclusively as a cytoplasmic structure. These findings
also reveal new mechanistic insights into the clinical combinations of DNA damaging agents with anti-MT
poisons in cancer therapy. In this project, we will further reveal detailed mechanisms via which Kif2C
modulates the mobility of DSBs; we will uncover how Kif2C acts in concert with chromatin remodelers and
other MT regulators to govern the dynamic chromatin compaction at damage chromatin; we will
functionally characterize ATM-mediated Kif2C phosphorylation, and regulation of MT stabilization after
DNA damage. Together, the project will potentially provide paradigm shifting additions to both the DDR
and MT biology, and improve our understanding of how the cell coordinates various cellular components
and mechanisms to maintain genomic stability and cell homeostasis after DNA damage.
DNA损伤,特别是DNA双链断裂(DSB),对细胞存活具有不利影响,
基因组稳定性作为对DNA损伤的反应,细胞激活了几个进化上保守的
修复DNA损伤、停止细胞增殖或诱导细胞死亡的机制。这些监视
机制,统称为DNA损伤反应(DDR),构成了一个重要的病因
许多人类疾病的因素,尤其是癌症。此外,解除武装、复员和重返社会方案是实现这一目标的一个关键决定因素。
使用辐射和其他DNA损伤剂的癌症治疗的治疗结果。长期
我们实验室的目标是使用全面的方法来描绘新的DDR因素和机制。
实验工具,从而揭示癌症进展和治疗的新见解。在最近的一
为了系统地鉴定DSB“修复体”的新组分,我们鉴定了Kif 2C和几个
其他MT调节剂作为潜在的DSB相关蛋白。Kif 2C被迅速募集到DNA损伤位点
并在DSB修复中起重要作用。引人注目的是,Kif 2C介导DSB的空间运动,
控制DNA损伤诱导的染色质重塑。Kif 2C的这些功能在很大程度上依赖于
其MT解聚酶活性,并可能通过与其他MT调节剂的协调来实现。对
另一方面,DNA损伤调节Kif 2C磷酸化和MT稳定化。这些发现
提出了一种新的细胞器间串扰之间的MT组件和DDR机制,不同的
从传统的观点来看,MT仅作为细胞质结构发挥作用。这些发现
还揭示了DNA损伤剂与抗MT的临床组合的新机制见解
癌症治疗中的毒药在这个项目中,我们将进一步揭示Kif 2C
调节DSB的流动性;我们将揭示Kif 2C如何与染色质重塑和
其他MT调节剂来控制损伤染色质处的动态染色质压实;我们将
在功能上表征ATM介导的Kif 2C磷酸化,以及在MT稳定化后的调节。
DNA损伤。总之,该项目将有可能为复员方案提供范式转移补充,
和MT生物学,并提高我们对细胞如何协调各种细胞成分的理解
以及在DNA损伤后维持基因组稳定性和细胞内稳态的机制。
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 }}
Aimin Peng其他文献
Aimin Peng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('Aimin Peng', 18)}}的其他基金
Greatwall in replication stress/DNA damage responses and oral cancer resistance
长城在复制应激/DNA损伤反应和口腔癌抵抗中的作用
- 批准号:
10991546 - 财政年份:2024
- 资助金额:
$ 4.46万 - 项目类别:
Greatwall in replication stress/DNA damage responses and oral cancer resistance
长城在复制应激/DNA损伤反应和口腔癌抵抗中的作用
- 批准号:
10175963 - 财政年份:2021
- 资助金额:
$ 4.46万 - 项目类别:
Greatwall in replication stress/DNA damage responses and oral cancer resistance
长城在复制应激/DNA损伤反应和口腔癌抵抗中的作用
- 批准号:
10545740 - 财政年份:2021
- 资助金额:
$ 4.46万 - 项目类别:
The novel role of microtubule regulators in the DNA damage response
微管调节剂在 DNA 损伤反应中的新作用
- 批准号:
10549300 - 财政年份:2021
- 资助金额:
$ 4.46万 - 项目类别:
The novel role of microtubule regulators in the DNA damage response
微管调节剂在 DNA 损伤反应中的新作用
- 批准号:
10524123 - 财政年份:2021
- 资助金额:
$ 4.46万 - 项目类别:
The novel role of microtubule regulators in the DNA damage response
微管调节剂在 DNA 损伤反应中的新作用
- 批准号:
10312794 - 财政年份:2021
- 资助金额:
$ 4.46万 - 项目类别:
Greatwall in replication stress/DNA damage responses and oral cancer resistance
长城在复制应激/DNA损伤反应和口腔癌抵抗中的作用
- 批准号:
10383756 - 财政年份:2021
- 资助金额:
$ 4.46万 - 项目类别:
The novel role of microtubule regulators in the DNA damage response
微管调节剂在 DNA 损伤反应中的新作用
- 批准号:
10381156 - 财政年份:2021
- 资助金额:
$ 4.46万 - 项目类别:
相似海外基金
Exploring the effect of ATP hydrolysis on condensin ability to compact chromosomes
探索 ATP 水解对浓缩蛋白压缩染色体能力的影响
- 批准号:
364619 - 财政年份:2017
- 资助金额:
$ 4.46万 - 项目类别:
The Mechanism and Regulation of ATP Hydrolysis in a Viral Genome Packaging Motor
病毒基因组包装马达中 ATP 水解的机制和调控
- 批准号:
9327813 - 财政年份:2017
- 资助金额:
$ 4.46万 - 项目类别:
Analysis of coupling between substrate binding and ATP hydrolysis in canonical homo- and heterodimeric amino acid ABC import systems
经典同二聚体和异二聚体氨基酸 ABC 输入系统中底物结合与 ATP 水解之间的耦合分析
- 批准号:
315832426 - 财政年份:2016
- 资助金额:
$ 4.46万 - 项目类别:
Research Grants
Mechanisms of actin polymerization, ATP hydrolysis, and filament severing revealed by F-form crystal structures
F 型晶体结构揭示肌动蛋白聚合、ATP 水解和丝断裂的机制
- 批准号:
16K14708 - 财政年份:2016
- 资助金额:
$ 4.46万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
Identification of key residues for control of the coupling between ATP hydrolysis and substrate transport of an ABC transporter
鉴定控制 ABC 转运蛋白 ATP 水解和底物转运之间耦合的关键残基
- 批准号:
26840048 - 财政年份:2014
- 资助金额:
$ 4.46万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Multisubunit viral ATPases that couple ATP-hydrolysis to genome translocation
将 ATP 水解与基因组易位耦合的多亚基病毒 ATP 酶
- 批准号:
9754155 - 财政年份:2012
- 资助金额:
$ 4.46万 - 项目类别:
Multisubunit viral ATPases that couple ATP-hydrolysis to genome translocation
将 ATP 水解与基因组易位耦合的多亚基病毒 ATP 酶
- 批准号:
8238803 - 财政年份:2012
- 资助金额:
$ 4.46万 - 项目类别:
Multisubunit viral ATPases that couple ATP-hydrolysis to genome translocation
将 ATP 水解与基因组易位耦合的多亚基病毒 ATP 酶
- 批准号:
8518398 - 财政年份:2012
- 资助金额:
$ 4.46万 - 项目类别:
Multisubunit viral ATPases that couple ATP-hydrolysis to genome translocation
将 ATP 水解与基因组易位耦合的多亚基病毒 ATP 酶
- 批准号:
8711498 - 财政年份:2012
- 资助金额:
$ 4.46万 - 项目类别:
Multisubunit viral ATPases that couple ATP-hydrolysis to genome translocation
将 ATP 水解与基因组易位耦合的多亚基病毒 ATP 酶
- 批准号:
8927018 - 财政年份:2012
- 资助金额:
$ 4.46万 - 项目类别: