Characterizing the LINE-1 Retrotransposition-Replication Conflict
表征 LINE-1 逆转录转座-复制冲突
基本信息
- 批准号:10634604
- 负责人:
- 金额:$ 39.68万
- 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:2020-07-15 至 2025-06-30
- 项目状态:未结题
- 来源:
- 关键词:AffectBARD1 geneBRCA1 geneBindingBiochemicalBiological AssayCRISPR/Cas technologyCancer Cell GrowthCell NucleusCell SurvivalCell physiologyCellsCodeComplementComplexConflict (Psychology)CytostaticsDNADNA RepairDNA Repair GeneDNA Repair PathwayDNA Transposable ElementsDNA biosynthesisDNA replication forkDataDetectionFanconi Anemia-BRCA PathwayFanconi&aposs AnemiaFiberFoundationsFunding OpportunitiesGene MutationGenesGenomeGenomicsHumanImmunofluorescence ImmunologicInhibition of Cancer Cell GrowthInternationalKnock-outLengthLethal GenesLigationLong Interspersed ElementsMalignant NeoplasmsMapsMediatingMediatorMethodsMethylationMobile Genetic ElementsMolecularMutateMutationNormal CellNuclearOpen Reading FramesPathway interactionsPoly(ADP-ribose) Polymerase InhibitorPoly(ADP-ribose) PolymerasesProcessProteinsRNA-Binding ProteinsRNA-Directed DNA PolymeraseResearchRetrotranspositionRetrotransposonReverse TranscriptionRoleS phaseSeriesShort Interspersed Nucleotide ElementsSignal PathwaySignal TransductionSiteSystemTestingThe Cancer Genome AtlasTherapeuticTumor Suppressor GenesVisualizationbiological adaptation to stresscancer cellcancer genomecell growthcopingcytotoxicendonucleaseexperimental studyfitnessgenome-widein vivomutantnext generation sequencingoverexpressionpreventpromoterreplication stressrestraintsynthetic lethal interactiontranslocaseubiquitin ligase
项目摘要
Project Summary
Much of our genome is made up of interspersed repeats derived from the activities of mobile genetic elements.
There are subsets of these sequences that become activated in cancers. Our research lab and others have
shown that nearly half of cancers fail to restrain long interspersed element-1 (LINE-1, L1) sequences. L1 is an
active retrotransposon that codes for two proteins, an RNA binding protein (ORF1p) and a protein with
endonuclease and reverse transcriptase activities (ORF2p). Paradoxically, though these proteins are
pervasively expressed in many human cancers, they inhibit cell growth in culture. We have exciting new data
from genome-wide knockout screens demonstrating how tumor suppressor gene mutations found in cancers
enable them to survive and grow despite their expression of L1. More importantly, these screens have also
identified genes that become essential in cells coping with L1 expression. These synthetic lethal genes
represent unique molecular vulnerabilities for L1(+) cells. L1(+) cells require specific DNA repair pathways,
effective replication stress signaling pathways, and replication fork restart capabilities. Here, we will test the
hypothesis that these pathways are required to eliminate L1 insertion intermediates and prevent collisions
between these intermediates and DNA replication forks. This project will increase our understanding of how
cancer cells replicate their DNA. It could lay a foundation to leverage L1-associated DNA replication stress to
limit cancer cell growth.
项目摘要
我们的基因组大部分由散布的重复序列组成,这些重复序列源自可移动的遗传元件的活动。
这些序列的某些子集在癌症中被激活。我们的研究实验室和其他人已经
研究表明,近一半的癌症不能抑制长分布的Element-1(Line-1,L1)序列。L1是一个
活性反转录转座子,编码两种蛋白质,一种是RNA结合蛋白(ORF1p),另一种是
核酸内切酶和逆转录酶活性(ORF2p)。矛盾的是,尽管这些蛋白质
它们在许多人类癌症中普遍表达,在培养中抑制细胞生长。我们有令人振奋的新数据
来自全基因组的基因敲除筛选,展示了肿瘤抑制基因突变是如何在癌症中发现的
使它们在表达L1的情况下仍能存活和生长。更重要的是,这些屏幕还具有
确定了在应对L1表达的细胞中至关重要的基因。这些人工合成的致命基因
代表L1(+)细胞独特的分子脆弱性。L1(+)细胞需要特定的DNA修复途径,
有效的复制压力信号通路和复制分叉重启能力。在这里,我们将测试
假设这些通路是消除L1插入中间产物和防止碰撞所必需的
在这些中间体和DNA复制分叉之间。这个项目将增加我们对如何
癌细胞复制它们的DNA。它可以为利用L1相关DNA复制应激来
限制癌细胞生长。
项目成果
期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
LINE-1 retrotransposition and its deregulation in cancers: implications for therapeutic opportunities.
- DOI:10.1101/gad.351051.123
- 发表时间:2023-12-26
- 期刊:
- 影响因子:10.5
- 作者:Mendez-Dorantes, Carlos;Burns, Kathleen H
- 通讯作者:Burns, Kathleen H
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KATHLEEN H BURNS其他文献
KATHLEEN H BURNS的其他文献
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{{ truncateString('KATHLEEN H BURNS', 18)}}的其他基金
Consequences of retrotransposition on genome integrity
逆转录转座对基因组完整性的影响
- 批准号:
10736406 - 财政年份:2023
- 资助金额:
$ 39.68万 - 项目类别:
Characterizing the LINE-1 Retrotransposition-Replication Conflict
表征 LINE-1 逆转录转座-复制冲突
- 批准号:
10215445 - 财政年份:2020
- 资助金额:
$ 39.68万 - 项目类别:
Characterizing the LINE-1 Retrotransposition-Replication Conflict
表征 LINE-1 逆转录转座-复制冲突
- 批准号:
10440427 - 财政年份:2020
- 资助金额:
$ 39.68万 - 项目类别:
Opportunities for Pathology Trainees in Cancer Research
癌症研究病理学实习生的机会
- 批准号:
9006475 - 财政年份:2015
- 资助金额:
$ 39.68万 - 项目类别:
Mouse Models of Functional Insertion Polymorphisms
功能插入多态性的小鼠模型
- 批准号:
8423827 - 财政年份:2013
- 资助金额:
$ 39.68万 - 项目类别: