Abstract
Oncogenic fusion genes as the result of chromosomal rearrangements are important for understanding genome instability in cancer cells and developing useful cancer therapies. To date, the mechanisms that create such oncogenic fusion genes are poorly understood. Previously we reported an unappreciated RNA-driven mechanism in human prostate cells in which the expression of chimeric RNA induces specified gene fusions in a sequence-dependent manner. One fundamental question yet to be addressed is whether such RNA-driven gene fusion mechanism is generalizable, or rather, a special case restricted to prostate cells. In this report, we demonstrated that the expression of designed chimeric RNAs in human endometrial stromal cells leads to the formation of JAZF1-SUZ12, a cancer fusion gene commonly found in low-grade endometrial stromal sarcomas. The process is specified by the sequence of chimeric RNA involved and inhibited by estrogen or progesterone. Furthermore, it is the antisense rather than sense chimeric RNAs that effectively drive JAZF1-SUZ12 gene fusion. The induced fusion gene is validated both at the RNA and the genomic DNA level. The ability of designed chimeric RNAs to drive and recapitulate the formation of JAZF1-SUZ12 gene fusion in endometrial cells represents another independent case of RNA-driven gene fusion, suggesting that RNA-driven genomic recombination is a permissible mechanism in mammalian cells. The results could have fundamental implications in the role of RNA in genome stability, and provide important insight in early disease mechanisms related to the formation of cancer fusion genes.
Highlights
One of the most prominent genetic alterations in cancer is gene fusion resulting from chromosomal rearrangements [1]
Studies have reported the presence of fusion RNAs in individuals who were negative for chromosomal translocations
The observation, that fusion RNA could be present prior to fusion gene formation, raises the provocative hypothesis that fusion RNA, or any cellular RNA with sequence compositions resembling that of fusion RNA, could act as a template to mediate genomic rearrangement
Summary
One of the most prominent genetic alterations in cancer is gene fusion resulting from chromosomal rearrangements [1]. The observation, that fusion RNA could be present prior to fusion gene formation, raises the provocative hypothesis that fusion RNA, or any cellular RNA with sequence compositions resembling that of fusion RNA, could act as a template to mediate/ specify genomic rearrangement by annealing to their parental genes that are in close proximity (Fig 1A) [6,7,8,9,10]. Resolving such an RNA/DNA hybrid by DNA repair mechanisms may yield the final gene fusion. Despite the fundamental implications in cancer and mammalian genome stability, RNA-driven genomic rearrangements in mammalian cells remains controversial as it has been difficult to confirm
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