Abstract
We among others have recently demonstrated that normal cells produce “fusion mRNAs”. These fusion mRNAs do not derive from rearranged genomic loci, but rather they are derived from “early-terminated transcripts” (ETTs). Premature transcriptional termination takes place in intronic sequences that belong to “breakpoint cluster regions”. One important property of ETTs is that they exhibit an unsaturated splice donor site. This results in: (1) splicing to “cryptic exons” present in the final intron; (2) Splicing to another transcript of the same gene (intragenic trans-splicing), resulting in “exon repetitions”; (3) splicing to a transcript of another gene (intergenic trans-splicing), leading to “non-genomically encoded fusion transcripts” (NGEFTs). These NGEFTs bear the potential risk to influence DNA repair processes, since they share identical nucleotides with their DNA of origin, and thus, could be used as “guidance RNA” for DNA repair processes. Here, we present experimental data about four other genes. Three of them are associated with hemato-malignancies (ETV6, NUP98 and RUNX1), while one is associated with solid tumors (EWSR1). Our results demonstrate that all genes investigated so far (MLL, AF4, AF9, ENL, ELL, ETV6, NUP98, RUNX1 and EWSR1) display ETTs and produce transpliced mRNA species, indicating that this is a genuine property of translocating genes.
Highlights
One of the hallmarks in hemato-malignant disorders and solid tumors are gross chromosomal changes, termed reciprocal chromosomal translocations
As judged from rearrangements with either an immunoglobulin or a T-cell receptor gene, we assume that most gene rearrangements are based on an non-homologous end joining (NHEJ)-mediated process that normally occurs in the G0/1 phase of the cell cycle
We investigated public databases for known transcript variants of these genes. This led quickly to ETV6, NUP98, RUNX1 and EWSR1 which we investigated further
Summary
One of the hallmarks in hemato-malignant disorders and solid tumors are gross chromosomal changes, termed reciprocal (or balanced) chromosomal translocations. A cryptic promoter near MLL exon 12 allows re-initiation of RNA transcription to express solely the C-terminal portion of the MLL protein [13] These findings led to additional studies, where we systematically investigated a series of MLL fusion partner genes (AF4, AF9, ELL and ENL) to demonstrate again that all these genes display a similar feature, namely to produce ETTs in their corresponding breakpoint cluster regions. Assuming that the production of non-genomically encoded fusion transcripts (NGEFTs) is a physiological event that lead to novel cellular functions by using an evolutionary process (exon shuffling), we posed the question whether the production of NGEFTs in healthy cells may lead under certain circumstances to the generation of chromosomal translocation If so, it would perfectly explain why certain genes of our genome are recurrently involved in genomic rearrangements. We were able to confirm that these genes produce ETT’s, terminating in their corresponding breakpoint cluster regions, and confirmed ETT production as genuine property of genes involved in recurrent genetic recombination events
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