TULANE COBRE: GENETIC INSTABILITY, ENVIRONMENTAL ACTIVATION OF MOBILE ELEMENTS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。在整个进化过程中，移动元件的活动对基因组的形成产生了重大影响。在人类中，移动元素贡献了几乎一半的基因组质量。目前，只有回溯元件LINE-1和Alu SINE是活跃的。据估计，每200个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极大地促进了遗传疾病。由可移动元件的插入突变引起的遗传不稳定可能是致癌的一个促成因素。例子包括通过移动元件使c-myc基因和APC肿瘤抑制子失活，导致人类患者患乳腺癌和结肠癌。因此，逆转录因子在人类基因组中是有效的诱变剂。先前的数据表明，SINE的表达，可能还有Alu的活性，会对外界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。尽管移动元件具有致突变的潜力，但关于sin和逆行基因扩增机制方面的研究尚处于起步阶段。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sin样逆转录，以确定在细胞水平上控制SINE和逆转录假基因扩增机制的因素；2)确定转录物封顶和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基本了解外部因素对非自主逆转录机制的影响及其如何导致人类疾病和遗传不稳定。

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.