TULANE COBRE: GENETIC INSTABILITY, ENVIRONMENTAL ACTIVATION OF MOBILE ELEMENTS

TULANE COBRE：遗传不稳定性、移动元素的环境激活

• 批准号: 6972572
• 负责人: ASTRID M ROY-ENGEL
• 金额: $ 18.69万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-17 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6972572
• 关键词: cadmium; carcinogenesis; gene mutation; genetic regulation; neoplasm /cancer genetics; nickel; northern blottings; phosphorylation; polymerase chain reaction; protooncogene; site directed mutagenesis; tissue /cell culture

Throughout evolution, the activity of mobile elements has had a major influence in the shaping of genomes. In humans, mobile elements contribute almost half of the genomic mass. Currently, only the retroelements LINE-1 and the Alu SINE are active. One new L1 or Alu insertion is estimated to occur in every 200 humans born. These insertions in the genome have significantly contributed to genetic disease. The genetic instability caused by the insertional mutagenesis of mobile elements can be a contributing factor in carcinogenesis. Examples include the inactivation of the c-myc gene and the APC tumor suppressor by a mobile element that caused breast and colon cancer in human patients. Thus, retroelements are potent mutagens in the human genome. Previous data demonstrate that SINE expression, and possibly Alu activity, respond to external factors such as heat shock and stress. Therefore, environmental factors could have a major influence in the induction of genetic instability by stimulating the activity of these elements. Despite the mutagenic potential of mobile elements, studies concerning the mechanistic aspects of SINEs and retropseudogene amplification are in their initial stages. To be able to define how the environment modulates the activity of these elements, the retroposition mechanism needs to be resolved. The specific goals of this project include: 1) to use an improved version of the recently developed assay to monitor SINE-like retroposition in tissue culture for the determination of factors governing the mechanism of SINE and retropseudogene amplification at a cellular level, 2) to determine the role of transcript capping and SRP9/14 in SINE retroposition, and 3) to evaluate the mechanism by which cadmium and nickel affect retroposition. The long-term goal of this project is to gain a fiandamental understanding the influence of external factors on retroposition mechanism of non-autonomous and how it contributes to human disease and genetic instability.

在整个进化过程中，移动元素的活动对形态的形成产生了重大影响。 基因组。在人类中，移动元件贡献了几乎一半的基因组质量。目前，仅逆向元件 LINE-1 和 Alu SINE 处于活动状态。据估计，每 200 名出生的人中就会出现一个新的 L1 或 Alu 插入。基因组中的这些插入对遗传疾病有显着的影响。 由移动元件的插入突变引起的遗传不稳定性可能是致癌的一个促成因素。例子包括由可移动元件导致的 c-myc 基因和 APC 肿瘤抑制因子失活，导致人类患者患乳腺癌和结肠癌。因此，逆转录元件是人类基因组中有效的诱变剂。先前的数据表明，SINE 表达以及可能的 Alu 活性对热休克和应激等外部因素有反应。因此，环境因素可能通过刺激这些元素的活性而对诱导遗传不稳定性产生重大影响。尽管移动元件具有诱变潜力，但有关 SINE 和逆转录假基因扩增机制方面的研究仍处于初始阶段。为了能够定义环境如何调节这些元素的活动，需要解决逆向机制。 该项目的具体目标包括：1) 使用最近开发的检测方法的改进版本来监测组织培养中的 SINE 样逆转录，以确定细胞水平上控制 SINE 和逆转录假基因扩增机制的因素，2)确定转录加帽和 SRP9/14 在 SINE 逆转录中的作用，3) 评估镉和镍影响逆转录的机制。 该项目的长期目标是从根本上了解外部因素对非自主性逆行机制的影响以及它如何导致人类疾病和遗传不稳定性。