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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：
KATHLEEN H BURNS
金额：
$ 39.68万
依托单位：
DANA-FARBER CANCER INST
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：
https://reporter.nih.gov/project-details/10634604
关键词：
Affect BARD1 gene BRCA1 gene Binding Biochemical Biological Assay CRISPR/Cas technology Cancer Cell Growth Cell Nucleus Cell Survival Cell physiology Cells Code Complement Complex Conflict (Psychology)Cytostatics DNA DNA Repair DNA Repair Gene DNA Repair Pathway DNA Transposable Elements DNA biosynthesis DNA replication fork Data Detection Fanconi Anemia-BRCA Pathway Fanconi&apos s Anemia Fiber Foundations Funding Opportunities Gene Mutation Genes Genome Genomics Human Immunofluorescence Immunologic Inhibition of Cancer Cell Growth International Knock-out Length Lethal Genes Ligation Long Interspersed Elements Malignant Neoplasms Maps Mediating Mediator Methods Methylation Mobile Genetic Elements Molecular Mutate Mutation Normal Cell Nuclear Open Reading Frames Pathway interactions Poly(ADP-ribose) Polymerase Inhibitor Poly(ADP-ribose) Polymerases Process Proteins RNA-Binding Proteins RNA-Directed DNA Polymerase Research Retrotransposition Retrotransposon Reverse Transcription Role S phase Series Short Interspersed Nucleotide Elements Signal Pathway Signal Transduction Site System Testing The Cancer Genome Atlas Therapeutic Tumor Suppressor Genes Visualization biological adaptation to stress cancer cell cancer genome cell growth coping cytotoxic endonuclease experimental study fitness genome-wide in vivo mutant next generation sequencing overexpression prevent promoter replication stress restraint synthetic lethal interaction translocase ubiquitin 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是由源自移动的遗传元件活动的散布重复序列组成的。这些序列的子集在癌症中被激活。我们的研究实验室和其他实验室显示几乎一半的癌症不能抑制长散布元件-1（LINE-1，L1）序列。L1是一编码两种蛋白质的活性反转录转座子，一种RNA结合蛋白（ORF 1 p）和一种核酸内切酶和逆转录酶活性（ORF 2 p）。奇怪的是，虽然这些蛋白质在许多人类癌症中普遍表达，它们抑制培养物中的细胞生长。我们有令人振奋的新数据从全基因组敲除筛选中，使它们能够存活和生长，尽管它们表达L1。更重要的是，这些屏幕还确定了在应对L1表达的细胞中必不可少的基因。这些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，有效的复制应激信号通路和复制叉重启能力。在这里，我们将测试假设这些途径是消除L1插入中间体和防止碰撞所必需的这些中间体和DNA复制叉之间的联系这个项目将增加我们对如何癌细胞复制DNA这为进一步利用L1相关DNA复制应激，限制癌细胞生长。