Regulation of DNA replication kinetics by BRCA2 after DNA damage
DNA 损伤后 BRCA2 对 DNA 复制动力学的调节
基本信息
- 批准号:10278027
- 负责人:
- 金额:$ 34.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-07-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AftercareAllelesBRCA2 geneBindingBreastBreast Cancer CellBreast Cancer ModelCDC45L geneCancer EtiologyCell Cycle CheckpointCellsChemotherapy and/or radiationChromatinCisplatinComplexCoupledDNADNA DamageDNA Double Strand BreakDNA PrimaseDNA RepairDNA Replication DamageDNA Replication FactorDNA biosynthesisDNA replication forkDNA-Directed DNA PolymeraseDefectDevelopmentDouble Strand Break RepairFamilyGenesGenomeGenome StabilityGenomic InstabilityGerm-Line MutationInduced MutationKineticsLeadMCM10 geneMCM2 geneMalignant NeoplasmsMalignant neoplasm of ovaryMammalsMammary TumorigenesisMapsMediatingMitoticModalityMutant Strains MiceMutationOvarianPancreasPathway interactionsPatternPhenotypePhysiologicalPlatinumPlayPolymeraseProcessPrognosisProteinsRadiationRadioRegulationRelapseReplication ErrorReplication InitiationReplication OriginReportingResistanceRoleS PhaseSaltsSecond Primary CancersSiteTestingTimeTravelTumor SuppressionTumor Suppressor ProteinsXenograft Modelbasecancer cellcancer therapyconditional knockoutdesigngenome integrityhelicasehomologous recombinationinhibitor/antagonistinsightmembermutantnovel strategiesoverexpressionpreventradiation responseradioresistantrecruitrepairedreplication stressresponseskip lesiontriple-negative invasive breast carcinomatumortumorigenesis
项目摘要
Germline mutations in BRCA2 predispose carriers to breast, ovarian, pancreatic, and other cancers. The gene
encodes a very large protein that plays critical roles in genome integrity control by promoting homologous
recombination (HR)-mediated repair of DNA double strand breaks (DSBs), DNA damage-induced cell cycle
checkpoint, and stability of stalled DNA replication forks, etc. Besides, BRCA2 may play a direct role in DNA
replication, as its mutant cells have long been known to have the so-called radio-resistant DNA synthesis
(RDS) phenotype, which reflects a defect in the intra-S phase checkpoint, a mechanism that slows down DNA
replication after DNA damage presumably to allow time for DNA repair and prevent replication of damage
DNA. However, the potential role of BRCA2 in DNA replication initiation or elongation has not been defined. In
our preliminary studies, we found that BRCA2 interacts with an essential DNA replication factor, MCM10, and
that this interaction restrains replication fork progression, promotes fork stalling and sustains origin firing after
DNA damage. We hypothesize that BRCA2 regulates DNA replication kinetics after DNA damage through its
interaction with MCM10 and that a dysregulation of replication kinetics after DNA damage, or intra-S phase
checkpoint defect, leads to increased mutation rate, cancer development and therapy resistance. We propose
3 specific aims to test the hypotheses. In Aim 1, we will define the mechanisms of BRCA2 function in DNA
replication kinetics after DNA damage. In Aim 2, we will determine the role of the BRCA2-MCM10 interaction in
DNA replication fidelity and cancer cell response to DNA damaging therapies. In Aim 3, we will determine the
role of BRCA2-MCM10 interaction in spontaneous and radiation-induced tumor development. Our findings and
proposed studies will elucidate key mechanisms of BRCA2 function in DNA replication, provide new insights
into the regulation of replication kinetics after DNA damage, and define the impact of RDS and replication
kinetics dysregulation on cancer development and tumor relapse after radiation and chemotherapy.
BRCA2的种系突变使携带者易患乳腺癌、卵巢癌、胰腺癌和其他癌症。的基因
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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Bing Xia其他文献
Bing Xia的其他文献
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{{ truncateString('Bing Xia', 18)}}的其他基金
Project 2: Targeting DNA replication in BRCA-associated breast cancer
项目 2:针对 BRCA 相关乳腺癌中的 DNA 复制
- 批准号:
10396609 - 财政年份:2021
- 资助金额:
$ 34.48万 - 项目类别:
Project 2: Targeting DNA replication in BRCA-associated breast cancer
项目 2:针对 BRCA 相关乳腺癌中的 DNA 复制
- 批准号:
10599900 - 财政年份:2021
- 资助金额:
$ 34.48万 - 项目类别:
Regulation of DNA replication kinetics by BRCA2 after DNA damage
DNA 损伤后 BRCA2 对 DNA 复制动力学的调节
- 批准号:
10437881 - 财政年份:2021
- 资助金额:
$ 34.48万 - 项目类别:
Regulation of DNA replication kinetics by BRCA2 after DNA damage
DNA 损伤后 BRCA2 对 DNA 复制动力学的调节
- 批准号:
10633270 - 财政年份:2021
- 资助金额:
$ 34.48万 - 项目类别:
Role of PALB2 in the DNA damage response and breast cancer suppression
PALB2 在 DNA 损伤反应和乳腺癌抑制中的作用
- 批准号:
7741534 - 财政年份:2009
- 资助金额:
$ 34.48万 - 项目类别:
Role of PALB2 in the DNA Damage Response and Cancer Suppression
PALB2 在 DNA 损伤反应和癌症抑制中的作用
- 批准号:
10166774 - 财政年份:2009
- 资助金额:
$ 34.48万 - 项目类别:
Role of PALB2 in the DNA Damage Response and Cancer Suppression
PALB2 在 DNA 损伤反应和癌症抑制中的作用
- 批准号:
10408039 - 财政年份:2009
- 资助金额:
$ 34.48万 - 项目类别:
Role of PALB2 in the DNA damage response and breast cancer suppression
PALB2 在 DNA 损伤反应和乳腺癌抑制中的作用
- 批准号:
8078115 - 财政年份:2009
- 资助金额:
$ 34.48万 - 项目类别:
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