4.8 Article

RNA-mediated gene fusion in mammalian cells

Publisher

NATL ACAD SCIENCES
DOI: 10.1073/pnas.1814704115

Keywords

gene fusion; chimeric RNA; prostate cancer; R-loop; noncoding RNA

Funding

  1. NIH [DK56338, CA125123, R01EB013584]
  2. Cancer Prevention Research Institute of Texas (CPRIT) [RP150578]
  3. Duncan Cancer Center
  4. Dunn Gulf Coast Consortium for Chemical Genomics
  5. CPRIT training Grant [RP160283]
  6. Duncan Cancer Center Pilot grant
  7. CPRIT Grant HIHRRA [RP160795]

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One of the hallmarks of cancer is the formation of oncogenic fusion genes as a result of chromosomal translocations. Fusion genes are presumed to form before 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 the genesis of a fusion RNA precedes the fusion gene. The fusion RNA then guides the genomic rearrangements that ultimately result in a gene fusion. However, RNA-mediated genomic rearrangements in mammalian cells have 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: (i) specified by the sequence of chimeric RNA involved, (ii) facilitated by physiological hormone levels, (iii) permissible regardless of intrachromosomal (TMPRSS2-ERG) or interchromosomal (TMPRSS2-ETV1) fusion, and (iv) can occur in normal cells before 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 functions as the initiator RNA to induce TMPRSS2-ERG fusion. RNA-driven gene fusion demonstrated in this report provides important insight in early disease mechanisms, 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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