Genetic Dissection of BRCA1's Recombination Function
BRCA1重组功能的基因剖析
基本信息
- 批准号:7227822
- 负责人:
- 金额:$ 28.96万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-05-15 至 2009-04-30
- 项目状态:已结题
- 来源:
- 关键词:AddressB-LymphocytesBRCA1 geneBRCA2 geneBase Excision RepairsBindingBiochemicalBiochemical GeneticsBiochemical PathwayBiological AssayBiological ProcessCancer-Predisposing GeneCell Cycle CheckpointCell Cycle RegulationCell LineCell SurvivalCell physiologyCellsChickensComplexCruciform DNADNADNA BindingDNA DamageDNA RepairDefectDissectionFemaleGene ExpressionGenesGeneticGenetic EpistasisGenetic RecombinationGenetic TranscriptionGenetic screening methodGoalsLaboratoriesMapsMediatingMolecularMolecular GeneticsMolecular ProfilingMutationOncogenesPhenotypePrincipal InvestigatorProcessProtein RegionProteinsRNA ProcessingRad51 recombinaseRecombinant DNAResistanceRibosomal DNARoleSiteStructureTestingTranscriptTranscriptional RegulationTumor Suppressor GenesUpper armVertebratesWorkXRCC3 genehomologous recombinationmalignant breast neoplasmmutantmutation carrierprogramsprotein degradationprotein structurerecombinaserecombinational repairrepairedresearch studyresponse
项目摘要
DESCRIPTION (provided by applicant): Our goal is to understand the functions of BRCA1 that contribute to its role as a tumor suppressor gene. 80% of female mutation carriers will develop breast cancer in their lifetime. BRCA1 and the other major breast cancer susceptibility gene BRCA2 have been implicated in recombinational repair of DNA damage by promoting the assembly of the homologous recombinase RAD51 at damaged sites. BRCA1's function does not appear to be limited to promoting recombinational repair, however. A large amount of work has implicated BRCA1 in diverse biological processes suggesting that the protein is multifunctional. BRCA1 is a very large protein and interacts, directly or indirectly, with many proteins and with DNA. These different protein-protein and proten-DNA interactions have been mapped to different regions of BRCA1 suggesting a structure composed of functional modules. In spite of the large amount of work on the protein, there is relatively little known about how these different interactions relate to BRCA1's different cellular functions in recombinational repair, base-excision repair, cell cycle checkpoint control, and gene expression. Which regions of the protein contribute to a given function? How are the different functions of the functions related? Is DNA binding required for all BRCA1's functions or just a subset? Through what mechanism does BRCA1 contribute to resistance to agents that block replication fork progression? These questions are addressed using the chicken pre-B cell line DT40 because of the ease with which this line can be modified by molecular genetics. The aims of the project are as follows. 1. To analyze the phenotypes of a BRCA1-/- null mutant derivative of DT40 with respect to homologous recombination, sensitivity to DNA damage, cell cycle checkpoint control, and transcription regulation. These phenotypes will be compared to those conferred by mutation of the XRCC3 gene, which is also required for assembly of recombination complexes 2. To search for BRCA1 regulated transcripts by expression profiling and to characterize the function of a newly discovered BRCA1 regulated gene. 3. To develop a new assay for examining structural changes of stalled replication forks and determine BRCA1's role in these changes. 4. To construct and characterize a set of cell lines in which regions of BRCA1 are systematically deleted or altered to map functional domains of BRCA1 in the normal cellular context. 5. To use biochemical and genetic assays to map the regions of BRCA1 that contribute to its DNA binding activity and determine which functions of BRCA1 depend on this activity.
描述(由申请人提供):我们的目标是了解BRCA1作为肿瘤抑制基因的功能。80%的女性突变携带者会在一生中患上乳腺癌。BRCA1和其他主要乳腺癌易感基因BRCA2通过促进同源重组酶RAD51在受损部位的组装,参与了DNA损伤的重组修复。然而,BRCA1的S功能似乎并不局限于促进重组修复。大量研究表明BRCA1参与了多种生物学过程,表明该蛋白具有多功能。BRCA1是一种非常大的蛋白质,直接或间接地与许多蛋白质和DNA相互作用。这些不同的蛋白质-蛋白质和蛋白质-DNA相互作用被映射到BRCA1的不同区域,暗示了一个由功能模块组成的结构。尽管对该蛋白质进行了大量的研究,但对于这些不同的相互作用与BRCA1的S在重组修复、碱基切除修复、细胞周期检查点控制和基因表达中的不同功能之间的关系,人们知之甚少。蛋白质的哪些区域对特定的功能起作用?这些功能的不同功能之间是如何关联的?BRCA1‘S的所有功能都需要dna结合,还是只需要一个子集?BRCA1是通过什么机制导致对阻止复制分叉进展的药物产生抵抗的?这些问题是用鸡前B细胞系DT40来解决的,因为这一系可以很容易地通过分子遗传学进行修改。该项目的目标如下。1.从同源重组、对DNA损伤的敏感性、细胞周期检查点控制和转录调控等方面分析了DT40的BRCA1/-零突变衍生物的表型。这些表型将与XRCC3基因突变所产生的表型进行比较,XRCC3基因突变也是组装重组复合体所必需的。2.通过表达谱寻找BRCA1调控的转录本,并鉴定新发现的BRCA1调控基因的功能。3.建立一种新的检测停滞复制叉结构变化的方法,并确定BRCA1的S在这些变化中的作用。4.构建一组BRCA1区域被系统缺失或改变的细胞系,以在正常细胞环境中定位BRCA1的功能结构域。5.利用生化和遗传分析方法定位BRCA1的DNA结合活性的区域,并确定BRCA1的哪些功能依赖于这一活性。
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)
RAD51 up-regulation bypasses BRCA1 function and is a common feature of BRCA1-deficient breast tumors
- DOI:10.1158/0008-5472.can-07-0290
- 发表时间:2007-10-15
- 期刊:
- 影响因子:11.2
- 作者:Martin, Richard W.;Orelli, Brian J.;Bishop, Douglas K.
- 通讯作者:Bishop, Douglas K.
{{
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 }}
DOUGLAS K BISHOP其他文献
DOUGLAS K BISHOP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('DOUGLAS K BISHOP', 18)}}的其他基金
Mechanism of Dmc1-mediated Meiotic Recombination in Budding Yeast
Dmc1 介导的芽殖酵母减数分裂重组机制
- 批准号:
10330987 - 财政年份:2020
- 资助金额:
$ 28.96万 - 项目类别:
Mechanism of Dmc1-mediated Meiotic Recombination in Budding Yeast
Dmc1 介导的芽殖酵母减数分裂重组机制
- 批准号:
10550168 - 财政年份:2020
- 资助金额:
$ 28.96万 - 项目类别:
Separating the function of RAD51 in homologous recombination and replication
分离 RAD51 在同源重组和复制中的功能
- 批准号:
9241382 - 财政年份:2016
- 资助金额:
$ 28.96万 - 项目类别:
Meiotic Interactions of the RecA Homologue Dmc1
RecA 同源物 Dmc1 的减数分裂相互作用
- 批准号:
7889779 - 财政年份:2009
- 资助金额:
$ 28.96万 - 项目类别:
Genetic Dissection of BRCA1's Recombination Function
BRCA1重组功能的基因剖析
- 批准号:
6897601 - 财政年份:2003
- 资助金额:
$ 28.96万 - 项目类别:
Genetic Dissection of BRCA1's Recombination Function
BRCA1重组功能的基因剖析
- 批准号:
7059384 - 财政年份:2003
- 资助金额:
$ 28.96万 - 项目类别:
Genetic Dissection of BRCA1's Recombination Function
BRCA1重组功能的基因剖析
- 批准号:
6597895 - 财政年份:2003
- 资助金额:
$ 28.96万 - 项目类别:
相似海外基金
Characterizing RNA regulation in B lymphocytes
B 淋巴细胞中 RNA 调控的特征
- 批准号:
502601 - 财政年份:2024
- 资助金额:
$ 28.96万 - 项目类别:
Characterization of Streptococcus suis interactions with B lymphocytes
猪链球菌与 B 淋巴细胞相互作用的表征
- 批准号:
573206-2022 - 财政年份:2022
- 资助金额:
$ 28.96万 - 项目类别:
University Undergraduate Student Research Awards
Myocardial-associated B lymphocytes and inflammatory injury
心肌相关B淋巴细胞与炎症损伤
- 批准号:
10543825 - 财政年份:2022
- 资助金额:
$ 28.96万 - 项目类别:
Altered B lymphocytes Due to Tungstate Exposure
钨酸盐暴露导致 B 淋巴细胞发生改变
- 批准号:
RGPIN-2020-05899 - 财政年份:2022
- 资助金额:
$ 28.96万 - 项目类别:
Discovery Grants Program - Individual
The regulation of signaling and cytoskeletal rearrangements in B-lymphocytes
B 淋巴细胞信号传导和细胞骨架重排的调节
- 批准号:
RGPIN-2019-04911 - 财政年份:2022
- 资助金额:
$ 28.96万 - 项目类别:
Discovery Grants Program - Individual
Myocardial-associated B lymphocytes and inflammatory injury
心肌相关B淋巴细胞与炎症损伤
- 批准号:
10339541 - 财政年份:2022
- 资助金额:
$ 28.96万 - 项目类别:
Role and regulation of extracellular vesicles generated in response to stimulation of CD24 on B lymphocytes
B 淋巴细胞上 CD24 刺激产生的细胞外囊泡的作用和调节
- 批准号:
RGPIN-2022-03800 - 财政年份:2022
- 资助金额:
$ 28.96万 - 项目类别:
Discovery Grants Program - Individual
Exploring RNA helicase DDX the role of the1 at the crossroad of DNA repair processes in B lymphocytes
探索 RNA 解旋酶 DDX 在 B 淋巴细胞 DNA 修复过程十字路口的作用
- 批准号:
BB/X511560/1 - 财政年份:2022
- 资助金额:
$ 28.96万 - 项目类别:
Training Grant