Replication fork dynamics and repair by Rad51 paralogues after DNA alkylation
DNA 烷基化后 Rad51 旁系同源物的复制叉动力学和修复
基本信息
- 批准号:10621773
- 负责人:
- 金额:$ 33.51万
- 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:2019-09-01 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAlkylating AgentsAlkylationAnemiaAntigen-Presenting CellsBRCA2 geneBindingBiochemicalBiological AssayBypassCause of DeathCell Death InductionCellsCellular biologyCessation of lifeClustered Regularly Interspaced Short Palindromic RepeatsComplexDNADNA AlkylationDNA DamageDNA RepairDNA Repair GeneDNA SequenceDNA StructureDNA replication forkDNA sequencingDNA-(apurinic or apyrimidinic site) lyaseDNA-Protein InteractionDataDevelopmentEnvironmentEukaryotaExhibitsExposure toFanconi&aposs AnemiaFilamentGenesGeneticGenetic RecombinationGenome StabilityGenomic InstabilityHeritabilityHumanHuman Cell LineIn VitroIndividualInduced MutationIndustrializationInvadedKnock-outLearningLesionMalignant NeoplasmsMalignant neoplasm of ovaryMediatingMediatorMethodsMethyl MethanesulfonateMutateMutationNatureNucleoproteinsOutcomePathway interactionsPositioning AttributePredispositionProcessProteinsProtocols documentationRAD51C geneRad51 recombinaseRegulationRepair ComplexReplication OriginRiskRoleSaccharomyces cerevisiaeSaccharomycetalesSequence AnalysisSomatic MutationSourceSpecificityTestingToxic Environmental SubstancesUnited StatesWorkXRCC2 geneXRCC3 geneYeastsautonomously replicating sequencecancer predispositiongenotoxicityhomologous recombinationin vivoinnovationinsightmalignant breast neoplasmmembermutantnovelparalogous genepreventrecruitrepairedreplication stresstumorigenesis
项目摘要
7. Project Summary
Misrepair of DNA damage is a hallmark of cancer. We discovered that the budding yeast Shu complex is a
conserved regulator of DNA repair through a central role in Rad51 regulation. Rad51 functions during the high
fidelity homologous recombination pathway to find and invade a homologous template for repair and also
during replication fork protection and restart. Rad51 is tightly regulated in cells by accessory proteins,
collectively called the Rad51 mediators, including the Shu complex. In humans, misregulation of hRAD51 or
its mediators is associated with cancer predisposition (particularly breast and ovarian cancers) and Fanconi
anemia, which is also characterized by anemia and cancer. We found that disruption of the yeast Shu complex
leads to cellular death specifically upon exposure to alkylation induced DNA damage. Alkylation damage is
caused by a myriad of industrial and consumer-based sources and is pervasive in our environment. DNA
alkylation leads to replication stress and DNA damage. If DNA is alkylated during replication, then the
replication fork can stall or collapse, and many repair mechanisms can be utilized to tolerate, bypass, or repair
the damaged DNA. How a cell commits to a specific repair pathway is largely known. In budding yeast, the
Shu complex is critical in the processing of replication forks damaged by alkylating agents. This complex is
highly conserved throughout eukaryotes and contains the Rad51 paralogs, proteins that are structurally similar
to the central DNA repair protein Rad51 and are mutated in cancer. In this study, we aim to elucidate the role
of the yeast and human Shu complexes in repair of DNA alkylation damage at a replication fork. We are
testing the hypothesis that the Shu complex is a critical key regulator of DNA damage tolerance at a replication
fork by specifically recognizing alkylation induced DNA damage to promote Rad51-mediated template switch
and protect forks from double-strand break induction by AP endonucleases. Using what we learn in yeast to
quickly and efficiently identify key substrates, residues, and protein targets, we will expand our studies into
human cell lines where we will investigate the role of the human Shu complex in tolerance of alkylation
damage. In addition, we will identify at risk individuals harboring mutations in these important genes that may
be more sensitive to DNA alkylation damage and therefore susceptible to cancer. Collectively, these studies
will provide key insights into the role of the Shu complex in tolerance of DNA alkylation damage and elucidate
how this complex promotes error-free DNA repair to prevent genetic instability and cancer.
!
7.项目摘要
DNA损伤的错误修复是癌症的标志。我们发现芽殖酵母Shu复合体是一种
通过在Rad51调节中发挥中心作用的DNA修复的保守调节剂。Rad51功能在高
保真度同源重组途径,以找到并侵入用于修复的同源模板,
在复制分叉保护和重新启动期间。Rad51在细胞中受到辅助蛋白的严格调控,
统称为拉德51调解人,包括舒氏复合体。在人类中,hRAD 51或
它的介质与癌症易感性(特别是乳腺癌和卵巢癌)和范可尼有关。
贫血,其特征还在于贫血和癌症。我们发现酵母Shu复合物的破坏
特别是在暴露于烷基化诱导的DNA损伤时导致细胞死亡。烷基化损害是
由无数的工业和消费者为基础的来源,并在我们的环境中无处不在。DNA
烷基化导致复制应激和DNA损伤。如果DNA在复制过程中被烷基化,
复制分叉可能会停止或崩溃,并且可以利用许多修复机制来容忍、绕过或修复
受损的DNA细胞如何致力于特定的修复途径在很大程度上是已知的。在芽殖酵母中,
Shu复合物在被烷化剂破坏的复制叉的加工中是关键的。该复合物
在整个真核生物中高度保守,包含Rad51旁系同源物,即结构相似的蛋白质
中心DNA修复蛋白Rad51,并在癌症中发生突变。在这项研究中,我们的目的是阐明的作用,
酵母和人Shu复合物在复制叉处DNA烷基化损伤修复中的作用。我们
测试Shu复合物是复制时DNA损伤耐受性的关键关键调节剂的假设
通过特异性识别烷基化诱导的DNA损伤来促进Rad51介导的模板转换
并保护叉免受AP内切核酸酶的双链断裂诱导。利用我们在酵母中学到的东西
快速,有效地确定关键底物,残留物和蛋白质靶点,我们将扩大我们的研究,
人类细胞系,我们将研究人类Shu复合物在烷基化耐受性中的作用
损害此外,我们将确定在这些重要基因中携带突变的风险个体,
对DNA烷基化损伤更敏感,因此易患癌症。总的来说,这些研究
将提供关键的见解,舒复合物的作用,在耐受DNA烷基化损伤和阐明
这种复合物如何促进无错误的DNA修复,以防止遗传不稳定和癌症。
!
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Hrq1/RECQL4 regulation is critical for preventing aberrant recombination during DNA intrastrand crosslink repair and is upregulated in breast cancer.
- DOI:10.1371/journal.pgen.1010122
- 发表时间:2022-09
- 期刊:
- 影响因子:4.5
- 作者:
- 通讯作者:
{{
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 }}
Kara A Bernstein其他文献
Kara A Bernstein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('Kara A Bernstein', 18)}}的其他基金
RAD51 paralog function in cancer predisposition and genome integrity
RAD51 旁系同源物在癌症易感性和基因组完整性中的功能
- 批准号:
10745028 - 财政年份:2022
- 资助金额:
$ 33.51万 - 项目类别:
RAD51 paralog function in cancer predisposition and genome integrity
RAD51 旁系同源物在癌症易感性和基因组完整性中的功能
- 批准号:
10206963 - 财政年份:2021
- 资助金额:
$ 33.51万 - 项目类别:
RAD51 paralog function in cancer predisposition and genome integrity
RAD51 旁系同源物在癌症易感性和基因组完整性中的功能
- 批准号:
10372159 - 财政年份:2021
- 资助金额:
$ 33.51万 - 项目类别:
Replication fork dynamics and repair by Rad51 paralogs after DNA alkylation
DNA 烷基化后 Rad51 旁系同源物的复制叉动力学和修复
- 批准号:
10162586 - 财政年份:2019
- 资助金额:
$ 33.51万 - 项目类别:
Replication fork dynamics and repair by Rad51 paralogs after DNA alkylation
DNA 烷基化后 Rad51 旁系同源物的复制叉动力学和修复
- 批准号:
10307906 - 财政年份:2019
- 资助金额:
$ 33.51万 - 项目类别:
Replication fork dynamics and repair by Rad51 paralogues after DNA alkylation
DNA 烷基化后 Rad51 旁系同源物的复制叉动力学和修复
- 批准号:
10736647 - 财政年份:2019
- 资助金额:
$ 33.51万 - 项目类别:
Replication fork dynamics and repair by Rad51 paralogs after DNA alkylation
DNA 烷基化后 Rad51 旁系同源物的复制叉动力学和修复
- 批准号:
10404570 - 财政年份:2019
- 资助金额:
$ 33.51万 - 项目类别:
Replication fork dynamics and repair by Rad51 paralogues after DNA alkylation
DNA 烷基化后 Rad51 旁系同源物的复制叉动力学和修复
- 批准号:
9182822 - 财政年份:2015
- 资助金额:
$ 33.51万 - 项目类别:
Replication fork dynamics and repair by Rad51 paralogues after DNA alkylation
DNA 烷基化后 Rad51 旁系同源物的复制叉动力学和修复
- 批准号:
8812516 - 财政年份:2015
- 资助金额:
$ 33.51万 - 项目类别:
Mechanistic insights into the SHU complex and Sgs1 in DNA repair and replication
DNA 修复和复制中 SHU 复合物和 Sgs1 的机制见解
- 批准号:
8267761 - 财政年份:2009
- 资助金额:
$ 33.51万 - 项目类别:
相似海外基金
Differential resistance mechanisms to monofunctional vs bifunctional alkylating agents in glioma
神经胶质瘤对单功能烷化剂与双功能烷化剂的不同耐药机制
- 批准号:
10374792 - 财政年份:2021
- 资助金额:
$ 33.51万 - 项目类别:
Elucidation and prevention of the mechanism of hepatic sinusoidal obstruction syndrome (SOS) induced by DNA alkylating agents
DNA烷化剂诱发肝窦阻塞综合征(SOS)机制的阐明和预防
- 批准号:
21K15255 - 财政年份:2021
- 资助金额:
$ 33.51万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Differential resistance mechanisms to monofunctional vs bifunctional alkylating agents in glioma
神经胶质瘤对单功能烷化剂与双功能烷化剂的不同耐药机制
- 批准号:
10570900 - 财政年份:2021
- 资助金额:
$ 33.51万 - 项目类别:
Development of individualized therapy by elucidation of molecular mechanisms for hypermutation phenotype induced by treatment with alkylating agents in glioma
通过阐明神经胶质瘤中烷化剂治疗诱导的超突变表型的分子机制来开发个体化治疗
- 批准号:
18K09004 - 财政年份:2018
- 资助金额:
$ 33.51万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Reversing intrinsic cancer cell resistance to alkylating agents by histone deacetylase inhibition
通过组蛋白脱乙酰酶抑制逆转癌细胞对烷化剂的内在耐药性
- 批准号:
214657440 - 财政年份:2012
- 资助金额:
$ 33.51万 - 项目类别:
Research Grants
Rerouting alkylating agents to the mitochondria for cancer therapy
将烷化剂重新路由至线粒体用于癌症治疗
- 批准号:
247842 - 财政年份:2011
- 资助金额:
$ 33.51万 - 项目类别:
Studentship Programs
Novel approaches to enhance tumor cell cytotoxicity of alkylating agents
增强烷化剂肿瘤细胞细胞毒性的新方法
- 批准号:
8105413 - 财政年份:2010
- 资助金额:
$ 33.51万 - 项目类别:
Novel approaches to enhance tumor cell cytotoxicity of alkylating agents
增强烷化剂肿瘤细胞细胞毒性的新方法
- 批准号:
8271313 - 财政年份:2010
- 资助金额:
$ 33.51万 - 项目类别:
Novel approaches to enhance tumor cell cytotoxicity of alkylating agents
增强烷化剂肿瘤细胞细胞毒性的新方法
- 批准号:
8730259 - 财政年份:2010
- 资助金额:
$ 33.51万 - 项目类别:
Novel approaches to enhance tumor cell cytotoxicity of alkylating agents
增强烷化剂肿瘤细胞细胞毒性的新方法
- 批准号:
8676463 - 财政年份:2010
- 资助金额:
$ 33.51万 - 项目类别: