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

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.