FANCJ dependent pathways in replication stress
FANCJ dependent pathways in replication stress
批准号:
9605534
负责人:
Sharon B Cantor
金额:
$40.49万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-09-05 至 2023-08-31
关键词:
AcetylationAddressBRCA1 geneBRCA2 geneBindingBiochemical GeneticsBioinformaticsBiological AssayBreastBreast Cancer geneBypassCancer PatientCell ProliferationCell SurvivalCellsCisplatinClinicalComplexDNADNA DamageDNA Mismatch Repair Protein MLH1DNA RepairDNA Repair GeneDNA StructureDNA biosynthesisDNA lesionDNA replication forkDataDefectDiseaseElectron MicroscopyEngineeringEnsureEquilibriumFanconi Anemia-BRCA PathwayFanconi anemia proteinFanconi&aposs AnemiaFiberFunctional disorderGenesGenomeGenomic InstabilityGoalsHealthHereditary Breast CarcinomaHereditary Breast and Ovarian Cancer SyndromeKnowledgeLinkMLH1 geneMalignant NeoplasmsMalignant neoplasm of ovaryMismatch RepairModificationMolecularMutateMutationNull LymphocytesOncogenesOutcomePathway interactionsPatientsPhenotypePhosphorylationPlayProcessProteinsProteomicsRecoveryRegulationResearchResistanceRoleSMARCA3 geneSiteStressSupporting CellTestingTherapeuticTherapeutic InterventionTransitional CellTranslationsTumor Suppressionbiological adaptation to stresschemotherapygain of functiongene functiongenetic approachgenome integrityhelicaseimprovedinnovationinsightmutantrepairedsingle moleculetherapeutic developmenttranscription factortumor
中文摘要
项目概要:
在揭示复制应激中起作用的蛋白质和途径方面已经取得了很大的进展
反应特别是遗传性乳腺癌基因,以及范可尼贫血(FA)突变基因,
在复制应激反应中起作用。现在可以理解,它们在复制中的功能丧失
应激反应有助于相关肿瘤对化疗如顺铂的敏感性。
然而,BRCA-FA蛋白的独特功能在很大程度上是未知的。在这里,我们建议分析
DNA复制叉动力学,复制体成分,并确定具有特定缺陷的患者突变
在复制应激反应中。
为了确定细胞如何从有缺陷的复制转变为失调的复制,
表达不同突变形式的BRCA 1相关FANCJ,在乳腺癌/卵巢癌中也发生突变,
和FA。与BRCA 1类似,我们发现FANCJ的功能是保护复制分叉免于崩溃。
我们还发现,这种FANCJ分叉保护功能需要其与错配修复的直接交互
(MMR)蛋白质MLH 1。这一发现提供了关于为什么缺乏FANCJ-MLH 1相互作用的细胞不能
从复制压力中恢复。我们还鉴定了假定的功能获得性FANCJ突变体,如
BRCA 1-相互作用缺陷突变体,规避复制压力,保持叉完整,并赋予超
对复制应激诱导剂的抗性。在目标1中,我们将试图定义FANCJ互动如何指导
DNA复制叉动力学。鉴于FANCJ定位于复制叉,取代蛋白质,
解开DNA,我们假设破坏与失调的复制不仅反映了DNA的变化,
结构,而且在DNA复制叉中发现的蛋白质。在目标2中,我们将寻求确定如何
FANCJ有助于复制体的组成,在未受到挑战的和在强调复制叉。
复制应激诱导FANCJ蛋白相互作用和翻译后修饰的变化。一些
这些变化发生在我们发现的癌症患者的突变位点。在目标3中,我们将寻求
抗复制应激的FANCJ突变体诱导的变化揭示了调控FANCJ的机制
在癌症中失去的功能。总的来说,通过定义细胞如何屈服于-或生存-毒性DNA损伤,
通常会干扰复制,我们将深入了解细胞从
在癌症中有缺陷到失调的复制。
!
英文摘要
Project Summary:
Great progress has been made in uncovering the proteins and pathways that function in the replication stress
response. In particular, the hereditary breast cancer genes, as well as genes mutated in Fanconi anemia (FA)
function in the replication stress response. It is now understood that loss of their function in the replication
stress response contributes to the sensitivity of associated tumors to chemotherapies, such as cisplatin.
However, the distinct functions for the BRCA-FA proteins are largely unknown. Here, we propose to analyze
DNA replication fork dynamics, replisome components, and identify patient mutations that have specific defects
in the replication stress response.
To define how a cell transitions from defective to dysregulated replication, we have engineered cells
expressing different mutant versions of the BRCA1-associated FANCJ also mutated in breast/ovarian cancer
and FA. Similar to BRCA1, we have uncovered that FANCJ functions to protect replication forks from collapse.
We also found that this FANCJ fork protection function requires its direct interaction with the mismatch repair
(MMR) protein, MLH1. This finding provides insight as to why cells lacking the FANCJ-MLH1 interaction fail to
recover from replication stress. We have also identified putative gain-of-function FANCJ mutants, such as the
BRCA1-interaction defective mutant, that circumvent replication stress, keep forks intact, and confer hyper-
resistance to replication stress inducing agents. In Aim 1, we will seek to define how FANCJ interactions direct
DNA replication fork dynamics. Given that FANCJ localizes to replication forks, displaces proteins, and
unwinds DNA, we hypothesize that disrupted vs dysregulated replication will reflect not only changes in DNA
structures, but also the proteins found at DNA replication forks. In Aim 2, we will seek to determine how
FANCJ contributes to the composition of the replisome in both unchallenged and at stressed replication forks.
Replication stress induces changes to FANCJ protein interactions and post-translation modifications. Some of
these changes occur at sites we found to be mutated in cancer patients. In Aim 3, we will seek to generate
FANCJ mutants resistant to replication stress induced changes to uncover mechanisms regulating FANCJ
function that are lost in cancer. Collectively, by defining how cells succumb to- or survive- toxic DNA damage
that normally interferes with replication, we will gain insight towards mechanisms transitioning cells from
defective to dysregulated replication in cancer.
!
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
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批准号:10362554
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项目类别:
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资助金额:$45.55万
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财政年份:2020
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负责人:Sharon B Cantor
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依托单位:
Defining BRCA replication dysfunction in therapy response
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资助金额:$55.59万
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财政年份:2020
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Targeting replication stress avoidance in cancer
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批准号:10608942
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项目类别:
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资助金额:$45.22万
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财政年份:2020
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依托单位:
Targeting replication stress avoidance in cancer
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批准号:10116341
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项目类别:
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资助金额:$46.76万
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财政年份:2020
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依托单位:
Defining BRCA replication dysfunction in therapy response
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批准号:10412057
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项目类别:
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资助金额:$54.48万
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财政年份:2020
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负责人:Sharon B Cantor
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依托单位:
FANCJ dependent pathways in replication stress
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批准号:10219989
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项目类别:
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资助金额:$35.87万
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财政年份:2018
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负责人:Sharon B Cantor
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依托单位:
FANCJ dependent pathways in replication stress
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批准号:10012292
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项目类别:
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资助金额:$3.69万
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财政年份:2018
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负责人:Sharon B Cantor
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依托单位:
FANCJ dependent pathways in replication stress
-
批准号:10462515
-
项目类别:
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资助金额:$35.64万
-
财政年份:2018
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负责人:Sharon B Cantor
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依托单位:
Identifying Biomarkers of Cisplatin Resistance Mechanisms in Ovarian Cancer
-
批准号:9277423
-
项目类别:
-
资助金额:$34.76万
-
财政年份:2014
-
负责人:Sharon B Cantor
-
依托单位:
Identifying Biomarkers of Cisplatin Resistance Mechanisms in Ovarian Cancer
-
批准号:8877458
-
项目类别:
-
资助金额:$34.76万
-
财政年份:2014
-
负责人:Sharon B Cantor
-
依托单位:
Identifying Biomarkers of Cisplatin Resistance Mechanisms in Ovarian Cancer
-
批准号:8761053
-
项目类别:
-
资助金额:$34.52万
-
财政年份:2014
-
负责人:Sharon B Cantor
-
依托单位:
BACH1/FANCJ Checkpoint, Recombination, and Chemoresistance
-
批准号:7388296
-
项目类别:
-
资助金额:$30.88万
-
财政年份:2007
-
负责人:Sharon B Cantor
-
依托单位:
BACH1/FANCJ Checkpoint, Recombination, and Chemoresistance
-
批准号:8114972
-
项目类别:
-
资助金额:$32.39万
-
财政年份:2007
-
负责人:Sharon B Cantor
-
依托单位:
BACH1/FANCJ Checkpoint, Recombination, and Chemoresistance
-
批准号:7498956
-
项目类别:
-
资助金额:$30.88万
-
财政年份:2007
-
负责人:Sharon B Cantor
-
依托单位:
BACH1/FANCJ Checkpoint, Recombination, and Chemoresistance
-
批准号:7653729
-
项目类别:
-
资助金额:$30.88万
-
财政年份:2007
-
负责人:Sharon B Cantor
-
依托单位:
BACH1/FANCJ Checkpoint, Recombination, and Chemoresistance
-
批准号:7895046
-
项目类别:
-
资助金额:$30.88万
-
财政年份:2007
-
负责人:Sharon B Cantor
-
依托单位:
FUNCTIONAL ANALYSIS OF BRCA1
-
批准号:6173659
-
项目类别:
-
资助金额:$3.92万
-
财政年份:2000
-
负责人:Sharon B Cantor
-
依托单位:
FUNCTIONAL ANALYSIS OF BRCA1
-
批准号:2896488
-
项目类别:
-
资助金额:$3.67万
-
财政年份:1999
-
负责人:Sharon B Cantor
-
依托单位:
FUNCTIONAL ANALYSIS OF BRCA1
-
批准号:2634006
-
项目类别:
-
资助金额:$2.62万
-
财政年份:1998
-
负责人:Sharon B Cantor
-
依托单位:
海外基金