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Chimeric RNAs in cancer and normal physiology

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Traditionally, chimeric RNAs were considered to be exclusive to cancer cells. When occasionally observed in normal samples, they were usually considered to be transcriptional ‘noises,’ or artifacts due to template switching during the reverse transcription and/or Polymerase chain reaction (PCR) steps of experimentation. However, with the advances being made in next generation sequencing technologies and software tools, as well as the accumulation of new experimental evidences, increasing numbers of chimeric transcripts are being identified in noncancerous tissues and cells. Recent studies have also demonstrated functional relevance, for at least a subset of chimeric RNAs in normal physiology. The advances have resulted in an influx of knowledge; this knowledge indicates that chimeric RNAs are a component of basic biology, and thus challenging traditional dogma. In addition to chromosomal rearrangement, chimeric RNAs can also be formed via different molecular mechanisms including cis‐splicing of adjacent genes (cis‐SAGe) and trans‐splicing, as well as others. Little is known about the details of these noncanonical splicing processes. However, research in this new field promises to not only advance our basic understanding of the human genome and gene regulation, but also lead to improvements in clinical practice, especially in the areas of cancer diagnostics and treatment. WIREs RNA 2017, 8:e1427. doi: 10.1002/wrna.1427 This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing RNA in Disease and Development > RNA in Disease
Classification of different types of splicing. The two main classes are cis‐ and trans‐splicing (TS). Canonical cis‐splicing involves transcripts from one gene. Adjacent genes that transcribe in the same direction can also form chimeric RNAs, via the cis‐SAGe mechanism. In primitive organisms, TS usually occurs between a short leader sequence (SL) and the transcript of another gene; however, an SL is not required in all of the cases—joined transcripts can derive from different genes, via intergenic TS), or from different exons of the same gene, via intragenic TS, which includes sense–antisense chimeras, shown here. The latter also includes exon shuffling and exon repetition (not depicted in this figure).
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The formation of chimeric transcripts may result in the acquisition of a signal peptide sequence, which may result in the relocalization of newly created fusion proteins.
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Putative functions of chimeric RNAs. (a) Formation of a chimeric RNA can result in switching of the regulatory mechanism for the parental transcripts. The 5′ UTR is responsible for translational regulation, and the 3′ UTR is a known target site for many regulatory micro‐RNAs, which contribute to the regulation of mRNA stability, and protein translation. (b) Out‐of‐frame fusions can act as long noncoding RNAs, potentially exhibiting regulatory functions. (c) When the 5′ gene gains a premature stop codon due to a frame‐shift, the whole transcript may be subjected to a nonsense‐mediated decay, affecting the overall level of this transcript in the cell. (d) When the open reading frame is preserved during chimeric RNA formation, the transcript can be translated into a novel chimeric protein.
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Common characteristics of cis‐SAGe chimeras: (1) parental genes are usually separated by a relatively small distance, 8.5 –30.6 kb region, (2) 5′ gene is actively transcribed, and (3) the fusion transcripts tend to have the second‐to‐last exon of the 5′ gene joining to the second exon of the 3′ gene.
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Chimeric RNA formation patterns. (a) Chimeras between transcripts derived from adjacent genes tend to join the second‐to‐last exon of the 5′ gene to the second exon of the 3′ gene. (b) SL trans‐splicing (TS) relies on the existence of a leader sequence (SL) which is joined to the 5′ end of another transcript during a spliceosome‐mediated, TS event. (c, d, e) SL independent TS: intergenic TS, where joined transcripts derive from different genes (c) or intragenic TS, which includes exon repetition (d), exon shuffling (e), and sense–antisense chimeras (not depicted here) within the same gene transcripts.
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RNA Processing > Splicing Regulation/Alternative Splicing
RNA in Disease and Development > RNA in Disease

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