Mechanisms of Retrotransposon Replication

  • Gabriel, Abram (PI)

Project Details

Description

9317281 Gabriel Trypanosomal CRE1 and human L1 are members of the little understood family of mobile genes known as non-LTR retrotransposons that are widely distributed in mammals, insects, plants, trypanosomatids, and fungi. While evidence suggests that this class of transposon is involved in such diverse and fundamental processes as insertional mutagenesis, genetic disease initiation, pseudogene formation, and genome evolution, almost nothing is known about the mechanisms by which these elements transpose other than that they use RNA intermediates. Most non- LTR retrotransposons are dispersed throughout their host's genome. However, CRE1 and related elements in other trypanosomes have the unusual feature that they are inserted at a specific, conserved site within a set of tandemly duplicated genes. We propose to utilize a novel yeast expression system to study the biochemistry of the reverse transcriptase encoded by human L1 and to identify the basis for CRE1 site-specific insertion. Accomplishment of our specific aims will advance knowledge of the mechanisms involved in the replication of this poorly understood but biologically important class of retrotransposons. On a broader scale, the results will be relevant to questions concerning eukaryotic genome organization and evolution, as well as the pathogenesis of human genetic disease. %%% A variety of transposable genetic elements ('jumping genes') are found within the DNA of all organisms. Over 10% of human chromosomal DNA is made up of sequences that were copied from RNA into DNA using the enzyme reverse transcriptase (RT). This enzyme, first found in retroviruses, is now known to be essential for a large class of transposons to copy themselves and move to new genomic locations. We have shown that a functional gene for RT is normally found in human DNA as part of the transposon L1. We propose to study the biochemical properties of L1 RT to determine how it recognizes its own sequences and how it can copy other RNA back into DNA. Further, we propose to study an unusual property of a similar transposon, CRE1, from a protozoan parasite. CRE1 is only found inserted in a single region of its host's chromosomes, and the basis for site-specificity may give clues to the mechanisms it employs in its jumping. Our studies will help elucidate the workings of a poorly understood class of genetic elements which have been implicated in creating mutations, causing genetic disease, and stimulating species evolution. ***

StatusFinished
Effective start/end date1/15/946/30/97

Funding

  • National Science Foundation: $274,000.00

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