Mobile element mutagenesis as a driver of human cancers

移动元件突变是人类癌症的驱动因素

• 批准号: 10675557
• 负责人: Scott E Devine
• 金额: $ 34.64万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-02 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675557
• 关键词: Adult; Brain; Colorectal; Complement; DNA Insertion Elements; Data; Data Collection; Elements; Epithelium; Genome; Goals; Human; Human Genome; L1 Elements; Length; Lung; Malignant Neoplasms; Mediating; Methods; Methylation; Mission; Mobile Genetic Elements; Mutagenesis; Mutagens; Mutate; National Cancer Institute; Normal tissue morphology; Oncogenes; Pancreas; Regulation; Reporting; Repression; Resources; Retrotransposon; Role; Sampling; Somatic Cell; Source; Suggestion; The Cancer Genome Atlas; Tissues; Tumor Suppressor Genes; Tumor Tissue; Work; human disease; human tissue; novel; offspring; tumor; tumorigenesis

Project Summary. Human LINE-1 (L1) elements are autonomous retrotransposons that continue to produce new “offspring” L1 insertions in human genomes. Until recently, L1 elements were thought to be mobilized primarily in the germline and then silenced in somatic cells throughout adulthood. However, several recent reports have shown that L1 elements are active in at least some adult somatic tissues, including the brain and epithelial somatic tumors. These observations have led to the suggestion that L1 might play a role in initiating human cancers by mutating specific tumor suppressor genes and oncogenes in somatic cells. In the three aims of this proposal, we will further explore this hypothesis with an emphasis on studying the expression, regulation, and mobilization of the full-length L1 source elements that generate new L1 insertions. In Specific Aim 1, we will generate a comprehensive resource of full-length, human-specific L1 (FL-L1Hs) source elements that will be used throughout this proposal (Aims 1-3) to study the role of L1 mobilization in human tissues and tumors. In Specific Aim 2, we will examine the expression and regulation of FL-L1Hs elements that can evade somatic repression and will study the mechanism(s) whereby these elements manage to do this. Finally, in Specific Aim 3, we will examine the mobilization capacities of FL-L1Hs elements. Combined with the data generated in Aims 1 and 2, these data will allow us to better understand the expression, regulation, and mobilization of the FL-L1Hs elements that mutagenize the human genome. The successful completion of the three Aims of this study will transform our understanding of how mobile elements impact human diseases, including cancers.

项目摘要。 人类线1（L1）元素是自主逆转座子，继续产生新的 人类基因组中的“后代” L1插入。直到最近，L1元素被认为是动员的主要 在种系中，然后在整个成年期间在体细胞中沉默。但是，最近有几份报告 表明L1元素至少在某些成年体细胞组织中活跃，包括大脑和上皮 体肿瘤。这些观察结果提出了这样的建议，即L1可能在开始人类中发挥作用 通过在体细胞中突变特定的肿瘤抑制基因和癌基因来进行癌症。在这三个目标中 提案，我们将进一步探讨这一假设，重点是研究表达，调节和 动员的全长L1源元素生成新的L1插入。在特定目标1中，我们将 生成全长的，人类特异性L1（FL-L1HS）源元素的综合资源 在整个提案中使用（目标1-3）来研究L1动员在人体组织和肿瘤中的作用。 特定目的2，我们将检查可以逃避体细胞的FL-L1HS元素的表达和调节 抑制并将研究这些要素设法这样做的机制。最后，具体 AIM 3，我们将检查FL-L1HS元素的动员能力。结合生成的数据 目的1和2，这些数据将使我们能够更好地理解表达，调节和动员 FL-L1HS元素，使人类基因组诱变。这三个目标的成功完成 研究将改变我们对移动元素如何影响人类疾病（包括癌症）的理解。