Brca1-Mediated Suppression Of Retrotransposon Activity - Resubmission - 1

Brca1 介导的逆转录转座子活性抑制 - 重新提交 - 1

• 批准号: 9979202
• 负责人: Jef D BOEKE
• 金额: $ 23.77万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-07 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979202
• 关键词: Aging; Aphidicolin; BRCA1 Mutation; BRCA1 Protein; BRCA1 gene; BRCA2 gene; Back; Biochemical; Biological Assay; Biological Process; Breast; Cell physiology; Cells; Chromatin; Chromosomes; Clinical; DNA; DNA Damage; DNA Repair; DNA Repair Pathway; DNA biosynthesis; DNA replication fork; Defense Mechanisms; Deletion Mutation; Development; Disease; Event; Excision; Fanconi Anemia pathway; Frequencies; Gatekeeping; Genetic; Genome; Genome Stability; Genomic Instability; Human; Human Genome; Immunofluorescence Immunologic; Kinetics; Length; Life Cycle Stages; Ligation; Light; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Mammary Neoplasms; Mass Spectrum Analysis; Mediating; Messenger RNA; Microscopy; Molecular; Molecular Profiling; Movement; Mutation; Nature; Nuclear; Ovarian; Pancreatic Ductal Adenocarcinoma; Paste substance; Pathway interactions; Phenotype; Play; Point Mutation; Process; Proteins; RNA-Directed DNA Polymerase; Regulation; Replication-Associated Process; Reporter; Repression; Retrotransposition; Retrotransposon; Role; S Phase; Sampling; Site; Structure; Suppressor Mutations; The Cancer Genome Atlas; Tissues; Toxic effect; Transcriptional Regulation; Translations; Tumor Suppressor Proteins; Work; base; cancer genome; cancer initiation; chromatin remodeling; clinically relevant; deletion analysis; derepression; endonuclease; genome integrity; high throughput screening; homologous recombination; inhibitor/antagonist; insight; knock-down; malignant breast neoplasm; mutant; novel; overexpression; p53-binding protein 1; protein expression; protein profiling; recombinational repair; recruit; repaired; response; small hairpin RNA; tumor; tumor progression; tumorigenesis; whole genome

Project summary LINE-1/L1 retrotransposon is the only autonomous non-homologous retrotransposon active in the human genome. In the human genome, >100 copies of L1 are still able to move, in settings in which cellular defense mechanisms that repress retrotransposons are “breached”. Increasing evidence underscores the potential role of L1 protein expression and L1 activity in normal processes such as aging as well as in disease contexts like cancer initiation and progression. Genome instability is a key feature of many cancers and is increasingly considered not only a consequence of tumor development but a founding event for establishment and progression of cancer. Our recent work reveals that the combination of LINE-1 overexpression and BRCA1 knockdown leads to a novel form of genome instability we refer to as chromosome shattering. LINE-1, with its endonuclease and reverse transcriptase activity and its ability to “jump” within the genome increasing its copy number, is involved in chromatin instability at multiple levels. A whole genome screen aimed to identify factors that repress or support L1 movement (retrotransposition) established the tumor suppressor BRCA1 and the homologous recombination (HR) repair and Fanconi anemia pathways as potent inhibitors of L1 retrotransposition. The BRCA1 (BReast CAncer 1) gene is a well-established tumor suppressor the mutation or depletion of which is the cause of many breast, ovarian and other human cancers. The BRCA1 protein is a key player in the HR-based DNA repair pathway, a high fidelity repair process implemented by the cell during DNA replication to seamlessly correct and repair possibly deleterious damages. BRCA1 functions as a gatekeeper of genome integrity, an activity that has been extensively linked to cancer. BRCA1 has also been implicated in other molecular mechanisms such as chromatin remodeling, transcriptional control and translation regulation. Here we propose to explore the molecular mechanisms mediating BRCA1 suppression of L1 activity. Genetic, microscopy and biochemical approaches will be implemented to dissect functional interactions between BRCA1 and L1 retrotransposition. The identification of the basic mechanisms of BRCA1-mediated L1 suppression not only promises to clarify poorly understood facets of the L1 life-cycle but is also essential step to interpret L1’s role in the many cancers characterized by BRCA1 depletion.

项目摘要 LINE-1/L1逆转座子是人类活跃的唯一自主非同源逆转座子 基因组。在人类基因组中，> 100份L1的副本仍然能够移动，在蜂窝防御的设置中 反映逆转座子的机制被“违反”。越来越多的证据强调了潜在作用 L1蛋白表达和L1在正常过程中的活性，例如衰老以及疾病中的情况 癌症倡议和进展。基因组不稳定性是许多癌症的关键特征，并且越来越多 不仅被认为是肿瘤发育的结果，还考虑了建立和 癌症的进展。我们最近的工作表明，线1过表达和BRCA1的结合 敲低导致一种新型的基因组不稳定性形式，我们称为染色体破碎。及其1号线 核酸内切酶和逆转录酶活性及其在基因组中“跳跃”的能力增加其副本 数字参与多个级别的染色质不稳定性。 整个基因组筛查旨在识别反映或支持L1运动的因素（反转录） 建立了肿瘤抑制剂BRCA1和同源重组（HR）修复和fanconi贫血 途径是L1逆转录位的潜在抑制剂。 BRCA1（乳腺癌1）基因是一个良好的 肿瘤抑制器的突变或部署是许多乳房，卵巢和其他人的原因 癌症。 BRCA1蛋白是基于HR的DNA维修途径的关键参与者，这是高保真维修过程 在DNA复制过程中由细胞实施，以无缝纠正并修复可能的有害损害。 BRCA1充当基因组完整性的看门人，这种活性与癌症广泛相关。 在其他分子机制（例如染色质重塑，转录）中也暗示了BRCA1 控制和翻译调节。 在这里，我们建议探索介导BRCA1抑制L1活性的分子机制。遗传， 将实施显微镜和生化方法，以剖析BRCA1之间的功能相互作用 和L1逆转录。鉴定BRCA1介导的L1抑制的基本机制 只承诺阐明L1生命周期的不良方面，但也是解释L1的重要步骤 在以BRCA1部署为特征的许多癌症中的作用。