Molecular Modulator of RPA and RAD51 in Maintaining Genome Stability
RPA 和 RAD51 维持基因组稳定性的分子调节剂
基本信息
- 批准号:10541201
- 负责人:
- 金额:$ 32.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-12-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:AffinityAgingBRCA mutationsBRCA2 geneBindingBinding ProteinsBiochemicalBiologicalCRISPR/Cas technologyCell Cycle CheckpointCellsCellular Metabolic ProcessChIP-seqChromosome BreakageComplexDNADNA DamageDNA RepairDNA biosynthesisDNA lesionDNA replication forkDataDiseaseEnvironmental ExposureEquilibriumEventFailureFiberFunctional disorderGeneticGenomeGenome StabilityGenomic InstabilityGenomicsGoalsHumanHuman GenomeInvadedKnowledgeLearningLinkMaintenanceMalignant NeoplasmsMediatingMolecularMutagensMutationPARP inhibitionPathogenesisPoly(ADP-ribose) Polymerase InhibitorPositioning AttributeProteinsPublic HealthRad51 recombinaseRecoveryRepetitive SequenceResearchRoleSS DNA BPSingle-Stranded DNASiteStressSurfaceSystemTechniquesTestingTherapeuticWorkanti-cancer therapeuticcancer typecarcinogenesiscellular imagingdesignenvironmental agentgenome integritygenome-wideimprovedinnovationinsightmultidisciplinaryneoplastic cellnervous system disordernext generation sequencingnovelnovel strategiespreservationpreventprotective pathwayprotein complexrecruitrepairedreplication stressresponsetargeted cancer therapytumorigenesis
项目摘要
DNA damage constitutes a major threat to genetic integrity, and has thus been implicated in the
pathogenesis of cancer. Elucidating the mechanism safeguarding genome stability is important for
understanding the mechanism underlying carcinogenesis. Genome integrity is constantly threatened by
endogenous and exogenous agents arising from cellular metabolic processes as well as environmental
exposure, many of which impede normal DNA replication and cause replication fork stalling. Stalled forks need
to be properly repaired and rescued to prevent DNA lesions and genome instabilities that contribute to
tumorigenesis. To repair and rescue stalled replication, a network of proteins regulating DNA damage
response, DNA repair, replication, and cell cycle checkpoints are activated in response to stalled replication in
order to stabilize and restart stalled forks. However, the mechanism underlying fork repair is poorly understood.
Recent studies have revealed that the balance and dynamics of RAD51 and RPA at stalled forks are crucial for
fork stabilization and restart. Yet how RAD51 and RPA activities are modulated remains largely elusive. Our
recent findings suggest that the high-affinity single-stranded DNA binding protein complex known as CST may
be a new modulator for RPA and RAD51 at GC-rich repetitive sequences in response to replication stress. The
objective of this proposal is to understand the molecular relationship between CST, RAD51 and RPA in fork
rescue, with the goal to provide novel insights into how cells counteract DNA damage caused by genotoxins.
We propose to integrate advanced biochemical, cell biological, cell imaging, and next-gen sequencing
techniques to examine how CST may regulate RPA binding at stalled sites and maintain fork progression and
stability under stress (Aim 1), define how CST may modulate RAD51 activity at GC-rich stalled sites (Aim 2),
and characterize the regulatory role of a surface-exposed region of CST in regulating RAD51 and RPA
activities (Aim 3). Findings from the proposed research will provide novel information on the mechanism of
genome stability maintenance of rescuing stalled replication and preserving genome stability.
DNA 损伤对遗传完整性构成重大威胁,因此与
癌症的发病机制。阐明维护基因组稳定性的机制对于
了解致癌机制。基因组完整性不断受到威胁
细胞代谢过程以及环境因素产生的内源性和外源性因素
暴露,其中许多会阻碍正常的 DNA 复制并导致复制叉停滞。停转的货叉需要
得到适当的修复和拯救,以防止 DNA 损伤和基因组不稳定,从而导致
肿瘤发生。为了修复和挽救停滞的复制,调节 DNA 损伤的蛋白质网络
响应、DNA 修复、复制和细胞周期检查点被激活以响应停滞的复制
为了稳定并重新启动停滞的货叉。然而,人们对分叉修复的机制知之甚少。
最近的研究表明,RAD51 和 RPA 在停滞叉处的平衡和动态对于
货叉稳定并重新启动。然而,RAD51 和 RPA 活动的调节方式在很大程度上仍然难以捉摸。我们的
最近的研究结果表明,称为 CST 的高亲和力单链 DNA 结合蛋白复合物可能
是 RPA 和 RAD51 在富含 GC 的重复序列上响应复制应激的新调节剂。这
该提案的目的是了解 fork 中 CST、RAD51 和 RPA 之间的分子关系
救援,目的是提供关于细胞如何抵抗基因毒素引起的 DNA 损伤的新见解。
我们建议整合先进的生化、细胞生物学、细胞成像和下一代测序
技术来检查 CST 如何调节 RPA 在停滞位点的结合并维持分叉进展,以及
压力下的稳定性(目标 1),定义 CST 如何在富含 GC 的停滞位点调节 RAD51 活性(目标 2),
并表征 CST 表面暴露区域在调节 RAD51 和 RPA 中的调节作用
活动(目标 3)。拟议研究的结果将为机制提供新的信息
基因组稳定性维持,挽救停滞的复制并保持基因组稳定性。
项目成果
期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
The Intrinsically Disordered Region in the Human STN1 OB-Fold Domain Is Important for Protecting Genome Stability.
- DOI:10.3390/biology10100977
- 发表时间:2021-09-28
- 期刊:
- 影响因子:4.2
- 作者:Chai W;Chastain M;Shiva O;Wang Y
- 通讯作者:Wang Y
Crosstalk between CST and RPA regulates RAD51 activity during replication stress.
- DOI:10.1038/s41467-021-26624-x
- 发表时间:2021-11-05
- 期刊:
- 影响因子:16.6
- 作者:Lei KH;Yang HL;Chang HY;Yeh HY;Nguyen DD;Lee TY;Lyu X;Chastain M;Chai W;Li HW;Chi P
- 通讯作者:Chi P
CaMKK2 and CHK1 phosphorylate human STN1 in response to replication stress to protect stalled forks from aberrant resection.
- DOI:10.1038/s41467-023-43685-2
- 发表时间:2023-11-30
- 期刊:
- 影响因子:16.6
- 作者:Jaiswal, Rishi Kumar;Lei, Kai-Hang;Chastain, Megan;Wang, Yuan;Shiva, Olga;Li, Shan;You, Zhongsheng;Chi, Peter;Chai, Weihang
- 通讯作者:Chai, Weihang
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Weihang Chai其他文献
Weihang Chai的其他文献
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{{ truncateString('Weihang Chai', 18)}}的其他基金
Identification of a novel tumor suppressorof melanoma and UV-induced genome instability
黑色素瘤的新型肿瘤抑制因子和紫外线诱导的基因组不稳定性的鉴定
- 批准号:
10539561 - 财政年份:2022
- 资助金额:
$ 32.92万 - 项目类别:
Molecular Modulator of RPA and RAD51 in Maintaining Genome Stability
RPA 和 RAD51 维持基因组稳定性的分子调节剂
- 批准号:
10153729 - 财政年份:2019
- 资助金额:
$ 32.92万 - 项目类别:
Molecular Modulator of RPA and RAD51 in Maintaining Genome Stability
RPA 和 RAD51 维持基因组稳定性的分子调节剂
- 批准号:
10055860 - 财政年份:2019
- 资助金额:
$ 32.92万 - 项目类别:
Molecular Modulator of RPA and RAD51 in Maintaining Genome Stability
RPA 和 RAD51 维持基因组稳定性的分子调节剂
- 批准号:
10322742 - 财政年份:2019
- 资助金额:
$ 32.92万 - 项目类别:
Role of human CST in preventing telomere loss
人类 CST 在预防端粒丢失中的作用
- 批准号:
9145437 - 财政年份:2015
- 资助金额:
$ 32.92万 - 项目类别:
Mechanisms of fork restart in response to genotoxic stress
响应基因毒性应激的分叉重启机制
- 批准号:
8800247 - 财政年份:2014
- 资助金额:
$ 32.92万 - 项目类别:
Mechanisms of fork restart in response to genotoxic stress
响应基因毒性应激的分叉重启机制
- 批准号:
9551636 - 财政年份:2014
- 资助金额:
$ 32.92万 - 项目类别:
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