TULANE COBRE: GENETIC INSTABILITY, ENVIRONMENTAL ACTIVATION OF MOBILE ELEMENTS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在整个进化过程中，可移动元素的活动对基因组的形成产生了重大影响。在人类中，可移动的元素贡献了几乎一半的基因组质量。目前，只有逆行元件LINE-1和Alu Sine处于活动状态。据估计，每200名出生的人类中就会出现一个新的L1或Alu插入。基因组中的这些插入极大地导致了遗传性疾病。可移动元件的插入突变引起的遗传不稳定性可能是癌症发生的一个促成因素。例如，c-myc基因和APC肿瘤抑制因子被一种导致人类乳腺癌和结肠癌的移动元件失活。因此，反转录元件是人类基因组中的强大诱变剂。先前的数据表明，Sine的表达，以及可能的Alu活性，对外部因素如热休克和应激做出反应。因此，环境因素可能通过刺激这些元件的活性而在诱导遗传不稳定性方面产生重大影响。尽管可移动元件具有诱变潜力，但关于Sine和逆转录假基因扩增的机制方面的研究仍处于初级阶段。为了能够确定环境如何调节这些元素的活动，需要解决回溯机制。该项目的具体目标包括：1)使用最近发展的一种改进的方法来监测组织培养中的正弦样反转录，以确定在细胞水平上控制正弦和逆转录假基因扩增机制的因素；2)确定转录上限和SRP9/14在正弦反转中的作用；以及3)评估镉和镍影响反转的机制。本项目的长期目标是初步了解外界因素对非自主性基因回溯机制的影响，以及非自主性基因对人类疾病和遗传不稳定性的影响。

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.