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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。