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RNA-mediated Genomic Arrangements in Mammalian Cells

Sachin Kumar Gupta, Liming Luo, View ORCID ProfileLaising Yen
doi: https://doi.org/10.1101/151241
Sachin Kumar Gupta
Department of Pathology & Immunology, Department of Molecular & Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
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Liming Luo
Department of Pathology & Immunology, Department of Molecular & Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
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Laising Yen
Department of Pathology & Immunology, Department of Molecular & Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA
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  • For correspondence: yen@bcm.edu
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Summary

One of the hallmarks of cancer is the formation of oncogenic fusion genes as a result of chromosomal translocations. Fusion genes are presumed to occur prior to fusion RNA expression. However, studies have reported the presence of fusion RNAs in individuals who were negative for chromosomal translocations. These observations give rise to “the cart before the horse” hypothesis, in which fusion RNA precedes the fusion gene and guides the genomic rearrangements that ultimately result in gene fusions. Yet RNA-mediated genomic rearrangement in mammalian cells has never been demonstrated. Here we provide evidence that expression of a chimeric RNA drives formation of a specified gene fusion via genomic rearrangement in mammalian cells. The process is (1) specified by the sequence of chimeric RNA involved, (2) facilitated by physiological hormone levels, (3) permissible regardless of intra-chromosomal (TMPRSS2-ERG) or inter-chromosomal (TMPRSS2-ETV1) fusion, and (4) can occur in normal cells prior to malignant transformation. We demonstrate that, contrary to “the cart before the horse” model, it is the antisense rather than sense chimeric RNAs that effectively drive gene fusion, and that this disparity can be explained by transcriptional conflict. Furthermore, we identified an endogenous RNA AZI1 that acts as the ‘initiator’ RNA to induce TMPRSS2-ERG fusion. RNA-driven gene fusion demonstrated in this report provides important insight in early disease mechanism, and could have fundamental implications in the biology of mammalian genome stability, as well as gene editing technology via mechanisms native to mammalian cells.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted June 16, 2017.
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RNA-mediated Genomic Arrangements in Mammalian Cells
Sachin Kumar Gupta, Liming Luo, Laising Yen
bioRxiv 151241; doi: https://doi.org/10.1101/151241
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RNA-mediated Genomic Arrangements in Mammalian Cells
Sachin Kumar Gupta, Liming Luo, Laising Yen
bioRxiv 151241; doi: https://doi.org/10.1101/151241

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