Roles of Chromatin Modification in BRCA1 Dependent DNA Repair
染色质修饰在 BRCA1 依赖性 DNA 修复中的作用
基本信息
- 批准号:8623113
- 负责人:
- 金额:$ 32.2万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-04-01 至 2018-03-31
- 项目状态:已结题
- 来源:
- 关键词:ATP phosphohydrolaseAcetylationAddressAdultAffectAllelesBRCA1 MutationBRCA1 geneCell LineCellsChromatinChromatin StructureChromosomesClinicalComplexDNA Double Strand BreakDNA RepairDNA repair proteinDouble Strand Break RepairElementsEmbryoEquilibriumEventGeneticGenomic InstabilityHistone AcetylationHistone H4Histone deacetylase inhibitionHistonesIncidenceKnockout MiceLaboratoriesLysineMalignant NeoplasmsMalignant neoplasm of ovaryMapsMediatingMethylationModelingModificationMolecularMusMutatePhenotypePoly(ADP-ribose) PolymerasesProcessProteinsRadialRelative (related person)ResistanceRoleSystemTailTestingTumor Suppressionbasecarcinogenesischemotherapeutic agentchemotherapychromatin modificationchromatin proteindeep sequencingdrug sensitivityhigh riskhistone acetyltransferasehomologous recombinationinhibitor/antagonistmalignant breast neoplasmmutantpublic health relevancerecombinational repairresidenceresponsetumor
项目摘要
DESCRIPTION (provided by applicant): Chromatin modifications profoundly influence DNA repair, tumor suppression, and response to chemotherapy. A powerful genetic interaction between chromatin associated DNA repair proteins BRCA1 and 53BP1 exemplifies the importance of chromatin recognition to these phenomena. Heterozygous BRCA1 mutation confers a high risk of breast and ovarian cancer. BRCA1 mutant tumors lose the wildtype allele, rendering them effectively BRCA1 null. Consequently, BRCA1 mutant cancers respond clinically to poly(ADP)ribose polymerase inhibitors (PARPi) due to severely impaired homologous recombination (HR) mediated DNA repair. Impaired HR also underlies the embryonic lethality in BRCA1 knockout mice due to massive genomic instability. Strikingly, double null BRCA1-/-, 53BP1-/- mice survive to adulthood without increased cancer incidence, and show an order of magnitude less radial chromosome formation in response to PARPi than do BRCA1-/-, 53BP1+/+ cells. This remarkable genetic rescue occurs because 53BP1 deficiency restores HR in BRCA1 mutant cells, suggesting that inappropriate 53BP1 activity is causative for genomic instability and cancer formation in BRCA1 mutant cells. It is therefore of central importance to understand the molecular determinants that differentially control BRCA1 and 53BP1 DNA repair functions. We present evidence that histone acetylation is a critical determinant of a competition between BRCA1 and 53BP1 for accumulation at chromatin adjacent to DNA double strand breaks (DSBs). These findings support a model whereby sequential histone H4 tail acetylation and methylation regulate DNA repair mechanism utilization by segregating BRCA1 and 53BP1 to different chromatin territories adjacent to DSBs. We will investigate the molecular basi underlying these observations and seek to understand the relationship between chromatin structure and basic DNA repair mechanisms that influence responses to clinically important chemotherapeutic agents.
描述(由申请人提供):染色质修饰深刻影响DNA修复、肿瘤抑制和对化疗的反应。染色质相关的DNA修复蛋白BRCA 1和53 BP 1之间强大的遗传相互作用证实了染色质识别对这些现象的重要性。BRCA 1杂合子突变赋予乳腺癌和卵巢癌的高风险。 BRCA 1突变型肿瘤失去了野生型等位基因,使它们有效地BRCA 1无效。 因此,BRCA 1突变型癌症在临床上对聚(ADP)核糖聚合酶抑制剂(PARPi)有反应,这是由于同源重组(HR)介导的DNA修复严重受损。 受损的HR也是BRCA 1基因敲除小鼠由于大量基因组不稳定性而导致胚胎死亡的基础。 引人注目的是,双无效BRCA 1-/-,53 BP 1-/-小鼠存活至成年而没有增加癌症发病率,并且显示响应PARPi的放射状染色体形成比BRCA 1-/-,53 BP 1 +/+细胞少一个数量级。 这种显著的遗传拯救发生是因为53 BP 1缺陷恢复了BRCA 1突变细胞中的HR,这表明不适当的53 BP 1活性是BRCA 1突变细胞中基因组不稳定和癌症形成的原因。因此,了解差异控制BRCA 1和53 BP 1 DNA修复功能的分子决定因素至关重要。 我们提出的证据表明,组蛋白乙酰化是BRCA 1和53 BP 1之间的竞争,积累在染色质相邻的DNA双链断裂(DSB)的一个关键决定因素。这些发现支持了一个模型,即顺序组蛋白H4尾乙酰化和甲基化通过将BRCA 1和53 BP 1分离到邻近DSB的不同染色质区域来调节DNA修复机制的利用。 我们将研究这些观察结果的分子基础,并试图了解染色质结构和影响临床重要化疗药物反应的基本DNA修复机制之间的关系。
项目成果
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Roger A Greenberg其他文献
Assembling a protective shield
组装一个防护盾
- DOI:
10.1038/s41556-018-0152-x - 发表时间:
2018-07-26 - 期刊:
- 影响因子:19.100
- 作者:
Roger A Greenberg - 通讯作者:
Roger A Greenberg
Roger A Greenberg的其他文献
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{{ truncateString('Roger A Greenberg', 18)}}的其他基金
Genome Instability Induced Anti-Tumor Immune Responses
基因组不稳定性诱导的抗肿瘤免疫反应
- 批准号:
10626281 - 财政年份:2023
- 资助金额:
$ 32.2万 - 项目类别:
Tumor cell instrinsic DNA damage signaling to the immune response
肿瘤细胞内在 DNA 损伤向免疫反应发出信号
- 批准号:
10626282 - 财政年份:2023
- 资助金额:
$ 32.2万 - 项目类别:
Linking cancer cell metabolic reprogramming to the DNA repair mechanism
将癌细胞代谢重编程与 DNA 修复机制联系起来
- 批准号:
9040127 - 财政年份:2015
- 资助金额:
$ 32.2万 - 项目类别:
The RAP80-BRCC36 Deubiquitinating Complex in DNA Repair
DNA 修复中的 RAP80-BRCC36 去泛素化复合物
- 批准号:
9099237 - 财政年份:2015
- 资助金额:
$ 32.2万 - 项目类别:
Linking cancer cell metabolic reprogramming to the DNA repair mechanism
将癌细胞代谢重编程与 DNA 修复机制联系起来
- 批准号:
8879428 - 财政年份:2015
- 资助金额:
$ 32.2万 - 项目类别:
DNA Double Strand Break Chromatin Alterations and Genome Integrity
DNA 双链断裂染色质改变和基因组完整性
- 批准号:
8665995 - 财政年份:2013
- 资助金额:
$ 32.2万 - 项目类别:
DNA Double Strand Break Chromatin Alterations and Genome Integrity
DNA 双链断裂染色质改变和基因组完整性
- 批准号:
8820272 - 财政年份:2013
- 资助金额:
$ 32.2万 - 项目类别:
DNA double-strand break chromatin alterations and genome integrity
DNA 双链断裂染色质改变和基因组完整性
- 批准号:
10799132 - 财政年份:2013
- 资助金额:
$ 32.2万 - 项目类别:
Roles of Chromatin Modification in BRCA1 Dependent DNA Repair
染色质修饰在 BRCA1 依赖性 DNA 修复中的作用
- 批准号:
8479097 - 财政年份:2013
- 资助金额:
$ 32.2万 - 项目类别:
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