Role of TRF2 in DNA recombination
TRF2 在 DNA 重组中的作用
基本信息
- 批准号:10092177
- 负责人:
- 金额:$ 30.7万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-02-01 至 2023-01-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAllergic DiseaseAntibodiesAntibody ResponseB lymphoid malignancyB-Cell ActivationB-LymphocytesBacteriaBindingCell MaintenanceChromosomal translocationChromosome abnormalityChromosomesCytosine deaminaseDNADNA Double Strand BreakDNA RepairDNA Repair GeneDNA Repair PathwayDNA lesionDataDistalEnzyme ActivationEventExhibitsExtrinsic asthmaG22P1 geneGenerationsGenetic RecombinationGenomeGenome StabilityGenomic InstabilityGoalsGrantHeavy-Chain ImmunoglobulinsHematologic NeoplasmsHematological DiseaseIGH@ gene clusterIgEImmuneImmune responseImmune systemImmunoglobulin Class SwitchingImmunoglobulin GenesImmunoglobulin Switch RecombinationImmunoglobulinsLeadLesionMaintenanceMediatingMolecularMutateOncogenesPathogenesisPathway interactionsPlayProcessProductionProteinsProto-OncogenesRegulationRegulatory ElementResearch Project GrantsResearch ProposalsRoleTelomeric Repeat Binding Protein 2Tertiary Protein StructureTestingVirusactivation-induced cytidine deaminasec-myc Genesdesigngenomic aberrationsgenomic locuslarge cell Diffuse non-Hodgkin&aposs lymphomamouse modelnovelnovel therapeutic interventionpathogenpreventrepairedside effecttelomere
项目摘要
Antibody (immunoglobulin, Ig) class switch recombination (CSR) is an essential mechanism for the
diversification of humoral immune response through efficient generation of antibody isotypes that mediate
elimination of pathogens. CSR is a programmed deletional recombination event between DNA double strand
breaks in the Ig heavy chain gene locus (Igh). These DNA breaks are initiated by the mutagenic enzyme,
activation-induced cytidine deaminase (AID), which preferentially deaminates the Igh genes but also exhibits
‘off-target’ activity in non-Ig genes including proto-oncogenes. Hence, DNA breaks initiated by AID in off-target
regions of the genome lead to aberrant chromosome translocations between the Igh locus and oncogenes if
not correctly repaired. Indeed, such genomic aberrations are a hallmark of B cell malignancies. Accordingly the
goal of our research proposal is to characterize novel molecular mechanisms we have identified that regulate
the repair of DNA lesions initiated by AID during CSR. We recently discovered that the telomeric protein TRF2,
which is essential for protecting chromosome ends from DNA repair activity, is also needed for CSR. We
hypothesize that TRF2 is essential for the activity of DNA repair proteins involved in the processing of DNA
breaks initiated by AID during class switch recombination. Here we propose to extend our studies to identify
and characterize the molecular mechanisms utilized by TRF2 to control the CSR via the following specific
aims:
1. Determine the DNA repair proteins regulated by TRF2 during class switching.
2. Determine the molecular mechanisms used by TRF2 to control DNA repair during class switching.
3. Elucidate the mechanism by which TRF2 inhibits the formation of Igh-cmyc translocations.
Taken together, these studies will provide specific details into a novel mechanism that regulates immune
diversification in B cells and the maintenance of the genome stability during AID activation.
抗体(免疫球蛋白,IG)类别转换重组(CSR)是免疫球蛋白(Ig)的免疫应答的重要机制。
通过有效产生抗体同种型使体液免疫应答多样化,
消灭病原体。CSR是DNA双链之间的程序性缺失重组事件
IG重链基因座(Igh)断裂。这些DNA断裂是由诱变酶引发的,
活化诱导的胞苷脱氨酶(AID),其优先使Igh基因脱氨,但也表现出
非Ig基因(包括原癌基因)中的“脱靶”活性。因此,在脱靶细胞中由AID引发的DNA断裂
基因组的区域导致Igh基因座和癌基因之间的异常染色体易位,
没有正确修复。事实上,这种基因组畸变是B细胞恶性肿瘤的标志。相应地
我们的研究计划的目标是描述我们已经确定的调节
在CSR期间由AID启动的DNA损伤的修复。我们最近发现端粒蛋白TRF 2,
其对于保护染色体末端免于DNA修复活性是必需的,也是CSR所需要的。我们
假设TRF 2对于参与DNA加工的DNA修复蛋白的活性是必需的,
在类交换机重组期间由AID发起的中断。在这里,我们建议扩展我们的研究,以确定
并表征TRF 2通过以下特定途径控制CSR的分子机制
目的:
1.确定TRF 2在类别转换过程中调控的DNA修复蛋白。
2.确定TRF 2在类别转换过程中控制DNA修复的分子机制。
3.阐明TRF 2抑制Igh-cmyc易位形成的机制。
总之,这些研究将为调节免疫的新机制提供具体细节。
在B细胞中的多样化和在AID活化期间维持基因组稳定性。
项目成果
期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
PRMT5 Regulates DNA Repair by Controlling the Alternative Splicing of Histone-Modifying Enzymes.
- DOI:10.1016/j.celrep.2018.08.002
- 发表时间:2018-09-04
- 期刊:
- 影响因子:8.8
- 作者:Hamard PJ;Santiago GE;Liu F;Karl DL;Martinez C;Man N;Mookhtiar AK;Duffort S;Greenblatt S;Verdun RE;Nimer SD
- 通讯作者:Nimer SD
The uracil-DNA glycosylase UNG protects the fitness of normal and cancer B cells expressing AID.
- DOI:10.1093/narcan/zcaa019
- 发表时间:2020-09
- 期刊:
- 影响因子:5.1
- 作者:Safavi S;Larouche A;Zahn A;Patenaude AM;Domanska D;Dionne K;Rognes T;Dingler F;Kang SK;Liu Y;Johnson N;Hébert J;Verdun RE;Rada CA;Vega F;Nilsen H;Di Noia JM
- 通讯作者:Di Noia JM
Endocrine resistance and breast cancer plasticity are controlled by CoREST.
- DOI:10.1038/s41594-022-00856-x
- 发表时间:2022-11
- 期刊:
- 影响因子:16.8
- 作者:Garcia-Martinez, Liliana;Adams, Andrew M.;Chan, Ho Lam;Nakata, Yuichiro;Weich, Natalia;Stransky, Stephanie;Zhang, Zhao;Alshalalfa, Mohamed;Sarria, Leonor;Mahal, Brandon A.;Kesmodel, Susan B.;Celia-Terrassa, Toni;Liu, Zhijie;Minucci, Saverio;Bilbao, Daniel;Sidoli, Simone;Verdun, Ramiro E.;Morey, Lluis
- 通讯作者:Morey, Lluis
A licensing step links AID to transcription elongation for mutagenesis in B cells.
- DOI:10.1038/s41467-018-03387-6
- 发表时间:2018-03-28
- 期刊:
- 影响因子:16.6
- 作者:Methot SP;Litzler LC;Subramani PG;Eranki AK;Fifield H;Patenaude AM;Gilmore JC;Santiago GE;Bagci H;Côté JF;Larijani M;Verdun RE;Di Noia JM
- 通讯作者:Di Noia JM
Methylation of histone H3 lysine 36 is a barrier for therapeutic interventions of head and neck squamous cell carcinoma.
- DOI:10.1101/2023.11.06.565847
- 发表时间:2023-11
- 期刊:
- 影响因子:0
- 作者:Lucas D. Caeiro;Yuichiro Nakata;Rodrigo L. Borges;Liliana Garcia-Martinez;Carolina P. Bañuelos;S. Stransky;Ho Lam Chan;John P. Brabson;Diana Domínguez;Yusheng Zhang;Peter W. Lewis;Salvador Aznar-Benitah;Luisa Cimmino;Daniel Bilbao;Simone Sidoli;Ramiro E. Verdun;L. Morey
- 通讯作者:Lucas D. Caeiro;Yuichiro Nakata;Rodrigo L. Borges;Liliana Garcia-Martinez;Carolina P. Bañuelos;S. Stransky;Ho Lam Chan;John P. Brabson;Diana Domínguez;Yusheng Zhang;Peter W. Lewis;Salvador Aznar-Benitah;Luisa Cimmino;Daniel Bilbao;Simone Sidoli;Ramiro E. Verdun;L. Morey
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Ramiro Ernesto Verdun其他文献
Ramiro Ernesto Verdun的其他文献
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{{ truncateString('Ramiro Ernesto Verdun', 18)}}的其他基金
Role of Telomeric Proteins in Antibody Class Switch Recombination
端粒蛋白在抗体类别转换重组中的作用
- 批准号:
8915932 - 财政年份:2014
- 资助金额:
$ 30.7万 - 项目类别:
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