The role of microhomology-mediated end joining in Fanconi anemia pathogenesis
微同源介导的末端连接在范可尼贫血发病机制中的作用
基本信息
- 批准号:10367981
- 负责人:
- 金额:$ 45.41万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-02-01 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAllelesAmino AcidsAnemiaAnimal ModelAshkenazimBRCA1 geneBRCA2 geneBiologicalBiological AssayBone marrow failureCRISPR/Cas technologyCell LineCellsChemicalsChildCoiled-Coil DomainComplexDNADNA Double Strand BreakDNA RepairDNA Repair GeneDNA Repair PathwayDNA-Directed DNA PolymeraseDataDefectDevelopmentDiseaseEmbryoEmbryonic DevelopmentEquilibriumEtiologyExcisionFanconi&aposs AnemiaFlow CytometryFunctional disorderGenomic InstabilityHealthHematologyHematopoiesisHematopoietic stem cellsHereditary Breast and Ovarian Cancer SyndromeHumanHyperactivityImmunofluorescence MicroscopyIncidenceIndividualKnockout MiceLaboratoriesLifeMeasuresMediatingMolecularMusMusculoskeletalMutationOncogenesOrganismPALB2 genePathogenesisPathologicPathway interactionsPatientsPhenotypePopulationProcessProteinsReporterResectedRoleSeveritiesSingle-Stranded DNASubgroupSymptomsTestingTransgenic AnimalsTransplantationWorkcancer predispositiondevelopmental diseaseexperimental studygenetic approachhomologous recombinationinhibitorinsightleukemiamouse modelmutant mouse modelneonatal micenucleasep53-binding protein 1pre-clinicalprotein expressionrecombinational repairrecruitrepairedtherapeutic developmenttool
项目摘要
PROJECT SUMMARY
Children with Fanconi anemia (FA) demonstrate developmental disorders that include short stature,
musculoskeletal defects, cancer predisposition, bone marrow failure (BMF) and anemia. In a significant
proportion of cases, FA is associated with biallelic mutations in the hereditary breast and ovarian cancer (HBOC)
genes. Pre-clinical FA studies have largely relied on transgenic animal models. However, currently available FA
mouse models are born without developmental defects and hematological abnormalities have to be chemically
induced. Our laboratory has developed a new Brca1CC mutant mouse model with a 3-amino acid deletion in the
coiled-coil (CC) domain of Brca1 that specifically disrupts the Brca1-Palb2 association, resulting in loss of Rad51
loading and HR deficiency. Notably, Brca1CC homozygous mice are born at sub-Mendelian ratios, and neo-natal
mice demonstrate a range of phenotypes analogous to FA in humans, including short stature, BMF with severe
anemia, and adult mice develop leukemia. Therefore, Brca1CC mice closely resemble human FA and provide a
new tool to gain unprecedented insight into biological pathways that underpin FA etiology. Both homologous
recombination (HR) and microhomology-mediated end joining (MMEJ) are double stranded DNA break (DSB)
repair pathways that are initiated by DNA end resection, a process where DSBs are resected by nucleases to
form single stranded (ss)DNA regions. In preliminary data, we examined human FA patient cells, as well as
Brca1CC MEFs, for HR and MMEJ activity. Interestingly, while HR was lowered, MMEJ was hyperactivated in FA
cell lines. We now hypothesize that hyperactive DNA end resection and MMEJ promote the molecular
pathogenesis of FA. We will address the following Specific Aims: 1) identify DNA repair pathways that are
hyperactive in FA; 2) uncover mechanisms that promote FA embryonic development and pathogenesis; and 3)
examine the effects of MMEJ inhibition on FA pathogenesis. Collectively, the proposed experiments will yield
new insight into DNA repair mechanisms that promote genome instability and FA.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Neil Johnson其他文献
Neil Johnson的其他文献
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{{ truncateString('Neil Johnson', 18)}}的其他基金
Assessing DNA polymerase theta as a therapeutic target in BRCA1 mutant cancer
评估 DNA 聚合酶 θ 作为 BRCA1 突变癌症的治疗靶点
- 批准号:
10446399 - 财政年份:2022
- 资助金额:
$ 45.41万 - 项目类别:
Assessing DNA Polymerase Theta as a Therapeutic Target in BRCA1 Mutant Cancer
评估 DNA 聚合酶 Theta 作为 BRCA1 突变癌症的治疗靶点
- 批准号:
10884036 - 财政年份:2022
- 资助金额:
$ 45.41万 - 项目类别:
Assessing DNA polymerase theta as a therapeutic target in BRCA1 mutant cancer
评估 DNA 聚合酶 θ 作为 BRCA1 突变癌症的治疗靶点
- 批准号:
10579323 - 财政年份:2022
- 资助金额:
$ 45.41万 - 项目类别:
Dissecting BRCA1-PALB2 Activity in DNA Repair and Development
剖析 BRCA1-PALB2 在 DNA 修复和发育中的活性
- 批准号:
10664883 - 财政年份:2020
- 资助金额:
$ 45.41万 - 项目类别:
Dissecting BRCA1-PALB2 Activity in DNA Repair and Development
剖析 BRCA1-PALB2 在 DNA 修复和发育中的活性
- 批准号:
10229611 - 财政年份:2020
- 资助金额:
$ 45.41万 - 项目类别:
Dissecting BRCA1-PALB2 Activity in DNA Repair and Development
剖析 BRCA1-PALB2 在 DNA 修复和发育中的活性
- 批准号:
10453625 - 财政年份:2020
- 资助金额:
$ 45.41万 - 项目类别:
The role of microhomology-mediated end joining in Fanconi anemia pathogenesis
微同源介导的末端连接在范可尼贫血发病机制中的作用
- 批准号:
10580006 - 财政年份:2020
- 资助金额:
$ 45.41万 - 项目类别:
Dissecting BRCA1-PALB2 Activity in DNA Repair and Development
剖析 BRCA1-PALB2 在 DNA 修复和发育中的活性
- 批准号:
10388570 - 财政年份:2020
- 资助金额:
$ 45.41万 - 项目类别:
Compensatory mechanisms that promote homologous recombination in BRCA1 mutant cancers
促进 BRCA1 突变癌症同源重组的补偿机制
- 批准号:
10242152 - 财政年份:2019
- 资助金额:
$ 45.41万 - 项目类别:
Compensatory mechanisms that promote homologous recombination in BRCA1 mutant cancers
促进 BRCA1 突变癌症同源重组的补偿机制
- 批准号:
9762056 - 财政年份:2019
- 资助金额:
$ 45.41万 - 项目类别:
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