THE ROLE OF XPA AND ERCC1/XPF IN HEAVY METAL STIMULATION OF MOBILE ELEMENTS

XPA 和 ERCC1/XPF 在重金属刺激活动元件中的作用

• 批准号: 7960533
• 负责人: ASTRID M ROY-ENGEL
• 金额: $ 5.77万
• 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 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7960533
• 关键词: Affect; Biological Assay; Breast; Cadmium; Colon Carcinoma; Computer Retrieval of Information on Scientific Projects Database; Data; Elements; Environment; Environmental Risk Factor; Evolution; Funding; Genetic; Genetic Induction; Genetic Programming; Genome; Genomics; Goals; Grant; Heat-Shock Response; Heavy Metals; Hereditary Disease; Human; Human Genome; Insertional Mutagenesis; Institution; Mentors; Monitor; Mutagens; Nickel; Patients; Research; Research Personnel; Resources; Retroelements; Role; Shapes; Short Interspersed Nucleotide Elements; Source; Staging; Stress; Transcript; Tumor Suppressor Proteins; United States National Institutes of Health; XPA gene; c-myc Genes; cancer genetics; carcinogenesis; human disease; improved; tissue culture

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 在整个进化过程中，移动的元素的活动对基因组的形成产生了重大影响。在人类中，移动的元件贡献了几乎一半的基因组质量。目前，只有追溯元素LINE-1和Alu SINE处于活动状态。据估计，每200个出生的人类中就有一个新的L1或Alu插入。基因组中的这些插入对遗传疾病有很大的贡献。由移动的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c-myc基因和APC肿瘤抑制因子被移动的元件灭活，该元件导致人类患者的乳腺癌和结肠癌。因此，逆转录因子是人类基因组中的有效诱变剂。之前的数据表明，SINE表达以及可能的Alu活性会对热休克和应激等外部因素做出反应。因此，环境因素可能通过刺激这些元素的活性而对遗传不稳定性的诱导产生重大影响。尽管移动的元素具有致突变潜力，但关于西内斯和retropeptidogene扩增的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，需要解决追溯机制。该项目的具体目标包括：1）使用最近开发的测定的改进版本来监测组织培养物中的SINE样逆转录，以确定在细胞水平上控制SINE和逆转录酶基因扩增机制的因素，2）确定转录物加帽和SRP 9/14在SINE逆转录中的作用，（3）探讨镉和镍影响后移的机制。本项目的长期目标是深入了解外部因素对非自主基因易位机制的影响，以及它如何导致人类疾病和遗传不稳定性。