Regulation of stalled fork repair in mammalian cells
哺乳动物细胞中停滞叉修复的调节
基本信息
- 批准号:10434669
- 负责人:
- 金额:$ 35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-03 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaAffectAnemiaBRCA1 geneBRCA2 geneBindingBiological AssayBone marrow failureCRISPR/Cas technologyCell CycleCellsChildhoodClinicalComplementComplexCongenital AbnormalityCoupledDNADNA DamageDNA RepairDNA Replication DamageDNA StructureDNA biosynthesisDNA metabolismDNA replication forkDefectDiseaseEscherichia coliFanconi&aposs AnemiaGene ConversionGenesGeneticGenome StabilityGenomic InstabilityGenomicsHereditary Breast and Ovarian Cancer SyndromeIncidenceIndividualKnock-outLinkMalignant NeoplasmsMalignant neoplasm of ovaryMammalian CellMammalian ChromosomesMeasuresMediatingMolecularMusMutateMutationNonhomologous DNA End JoiningOrganOutcomePathologicPathway interactionsPatternPhenotypePhysiologicalPlayPreventionProcessRegulationReplication-Associated ProcessReporterRoleScaffolding ProteinSiteSolid NeoplasmStructureSurgical incisionsSusceptibility GeneTimeUrsidae FamilyWorkYeastsbrca genecancer genomecancer riskcancer therapychromatin immunoprecipitationdefined contributiondevelopmental diseaseembryonic stem cellendodeoxyribonuclease SceIendonucleasehomologous recombinationhuman diseaseinsightmalignant breast neoplasmmutantnew therapeutic targetnovelnucleasephysiologic modelpreservationpreventrepairedreplication stressscaffoldsuccesstargeted cancer therapytool
项目摘要
PROJECT SUMMARY
Error-free DNA repair initiated at the sites of replication fork stalling is critical to the prevention of genomic
instability in cycling cells. Defects in stalled fork repair have been directly implicated in cancer and other human
diseases. Fanconi Anemia (FA) is a rare, autosomal recessive (or X-linked) disease caused by inactivation of
any one of several FA genes. The clinical manifestations of FA include childhood anemia and progressive
bone marrow failure, together with short stature and congenital defects affecting a wide variety of organs. The
risk of cancer, including solid tumors, is elevated, with particularly high incidence of acute myelogenous
leukemia. The gene encoding a nuclease-coordinating scaffolding protein, SLX4/FANCP, is found mutated in
some individuals with Fanconi anemia and has been implicated in stalled fork repair through interactions with
the nucleases MUS81, XPF and SLX1. We adapted the Escherichia coli Tus/Ter replication fork arrest
complex for use in mammalian cells and have used it to provoke site-specific replication fork stalling and
homologous recombination (HR) at defined loci of a mammalian chromosome. We find that SLX4 plays a
crucial role in mediating error-free HR induced by Tus/Ter. This function is restricted to stalled fork repair and
is not a feature of HR induced by a conventional chromosomal double strand break. In work proposed here, we
will use novel tools developed by the Scully lab, to analyze how SLX4 regulates homologous recombination at
stalled replication forks. We will use physical and genomic assays to measure specific DNA structures that
form at the Tus/Ter-stalled fork and will determine whether SLX4 regulates the formation or metabolism of
these DNA structures. This project will identify the mechanisms by which SLX4 coordinates stalled fork
processing to preserve genome stability in the face of replication stress. Success in this work will lead to the
identification of new targets for therapy in cancer and other human diseases.
项目摘要
在复制叉停滞位点启动的无错误DNA修复对于预防基因组损伤至关重要。
循环电池的不稳定性。停滞的分叉修复缺陷直接与癌症和其他人类疾病有关。
疾病范可尼贫血(FA)是一种罕见的常染色体隐性(或X连锁)疾病,由失活的
几种FA基因之一。FA的临床表现包括儿童贫血和进行性贫血。
骨髓衰竭、身材矮小和影响多种器官的先天性缺陷。的
癌症(包括实体瘤)的风险升高,尤其是急性髓性白血病的发病率更高。
白血病发现编码核酸酶协调支架蛋白SLX 4/FANCP的基因突变,
一些患有范可尼贫血的个体,并通过与
核酸酶MUS 81、XPF和SLX 1。我们采用了大肠杆菌Tus/Ter复制叉停滞
复合物用于哺乳动物细胞,并已使用它来引发位点特异性复制叉停滞,
在哺乳动物染色体的限定基因座处的同源重组(HR)。我们发现,SLX 4发挥了
在介导Tus/Ter诱导的无错误HR中起关键作用。此功能仅限于失速叉修复,
不是由常规染色体双链断裂诱导的HR的特征。在这里提出的工作中,我们
将使用Scully实验室开发的新工具来分析SLX 4如何调节同源重组,
已停止的复制分叉。我们将使用物理和基因组分析来测量特定的DNA结构,
在Tus/Ter分叉处形成,并将决定SLX 4是否调节Tus/Ter分叉的形成或代谢。
这些DNA结构。该项目将确定SLX 4协调停滞的分叉的机制
处理以在面对复制压力时保持基因组稳定性。这项工作的成功将导致
用于癌症和其他人类疾病治疗的新靶点的鉴定。
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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Ralph Scully其他文献
Ralph Scully的其他文献
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{{ truncateString('Ralph Scully', 18)}}的其他基金
Stalled replication fork repair in cancer predisposition and cancertherapy
癌症易感性和癌症治疗中停滞的复制叉修复
- 批准号:
10517824 - 财政年份:2022
- 资助金额:
$ 35万 - 项目类别:
Stalled replication fork repair in cancer predisposition and cancertherapy
癌症易感性和癌症治疗中停滞的复制叉修复
- 批准号:
10681456 - 财政年份:2022
- 资助金额:
$ 35万 - 项目类别:
The DNA damage response of fast-cycling erythroblasts
快速循环有红细胞的DNA损伤反应
- 批准号:
10317904 - 财政年份:2021
- 资助金额:
$ 35万 - 项目类别:
The DNA damage response of fast-cycling erythroblasts
快速循环有红细胞的DNA损伤反应
- 批准号:
10473898 - 财政年份:2021
- 资助金额:
$ 35万 - 项目类别:
The DNA damage response of fast-cycling erythroblasts
快速循环有红细胞的DNA损伤反应
- 批准号:
10674034 - 财政年份:2021
- 资助金额:
$ 35万 - 项目类别:
Regulation of stalled fork repair in mammalian cells
哺乳动物细胞中停滞叉修复的调节
- 批准号:
10187598 - 财政年份:2019
- 资助金额:
$ 35万 - 项目类别:
Regulation of stalled fork repair in mammalian cells
哺乳动物细胞中停滞叉修复的调节
- 批准号:
10006891 - 财政年份:2019
- 资助金额:
$ 35万 - 项目类别:
A mouse model for studying homologous recombination fidelity during aging
用于研究衰老过程中同源重组保真度的小鼠模型
- 批准号:
8989960 - 财政年份:2015
- 资助金额:
$ 35万 - 项目类别:
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