Mechanisms of genome instability induced by transposable elements

Prof. Justin Blumenstiel, Department of Ecology & Evolutionary Biology
University of Kansas

Project dates: 2013-2014

Transposable elements (TEs) are selfish replicating elements that comprise about half of the human genome. Due to their proliferative and repetitive nature, they are a significant source of new mutation and chromosomal rearrangement. Studies over the past few years have provided growing evidence for TEs, through their mutator capacity, being an important contributor to cancer. Recent studies have also demonstrated that a genome defense mechanism mediated by small, silencing RNAs (piRNAs), limits potential TE damage by targeting TE transcripts for destruction. Under some circumstances, however, this mode of genome defense fails to control TE proliferation. In Drosophila, the mobilization of one single element family can result in global failure of TE control, chromosome damage and sterility. This syndrome of genome destabilization is known as hybrid dysgenesis. It is not clear how the mobilization of one element family can lead to cascading mobilization of other elements. A critical question is how this mobilization causes the machinery of genome defense by small RNAs to become compromised. The goal of this project is to test two specific models for how the piRNA machinery loses efficacy when TEs become mobilized. One model is that DNA damage itself is directly responsible for TE mobilization. A second model is that, as has been demonstrated with viruses, TEs encode suppressors of small RNA silencing. Thus, when one TE mobilizes, the piRNA machinery becomes directly antagonized, leading to the mobilization of other TEs. By testing these two models, we will provide significant insight into the mechanisms by which genome instability can be induced by TEs. In addition, by testing the TE encoded suppressor model, we may identify new potential mechanisms of oncogenesis.

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