Intergenically Spliced Chimeric RNAs in Cancer

Abstract

Gene fusions and their encoded products (fusion RNAs and proteins) are viewed as one of the hallmarks of cancer. Traditionally, they were thought to be generated solely by chromosomal rearrangements. However, recent discoveries of trans-splicing and cis-splicing events between neighboring genes, suggest that there are other mechanisms to generate chimeric fusion RNAs without corresponding changes in DNA. In addition, chimeric RNAs have been detected in normal physiology, complicating the use of fusions in cancer detection and therapy. On the other hand, "intergenically spliced" fusion RNAs represent a new repertoire of biomarkers and therapeutic targets. Here, we review current knowledge on chimeric RNAs and implications for cancer detection and treatment, and discuss outstanding questions for the advancement of the field.

Keywords: Chimeric RNA; cis-SAGe; fusion; intergenic splicing; trans-splicing.

Figure 1. Chimeric RNAs in Normal Tissues and Cells

RNA-Sequencing of (A) libraries covering 27 non-neoplastic human tissues; (B) human embryonic stem cells(ESC); (C) MCF10A breast epithelial cells; and (D) mesenchymal stem cell (MSC) collected at four differentiation steps (T1-T4) was analyzed by SoapFuse algorithms. Fusion events are shown by Circos plots. The fused transcripts are illustrated here as a line that connects two parental genes.

Figure 2. Key Figure. Production of Chimeric RNAs from Chromosomal Rearrangements and Intergenic Splicing

(A) Translocation. Rearrangement of parts from two non-homologous chromosomes can join two separated genes. (B) Inversion. Segment of a chromosome spanning two genes is reversed end to end, leading to the formation of fusion genes. (C) Deletion. Deleting interstitial part between two separate genes can result in gene fusion. (D) Cis-splicing between adjacent genes. The transcription machinery reads through two neighboring genes, transcribing in the same direction. After splicing, the exons from difference genes are spliced together to produce a chimeric RNA. (E) Intragenic trans-splicing. Two pre-mRNA transcripts from the same genomic locus participate in the process. The two pre-mRNA transcripts can be transcribed from the same strand or different strands. Intragenic trans-splicing can result in exon duplication of sense-antisense fusion. (F) Intergenic trans-splicing. Two pre-mRNA transcripts from two different genomic loci are spliced together.

Figure 3. Mechanisms of RNA-mediated DNA Rearrangement

(A) Chimeric RNAs act as repair templates for double strand DNA breakage. Chimeric RNAs pair with one strand of DNA at the double strand breakage site. The repair machinery uses chimeric RNA as the template, and the newly synthesized DNA will share sequence similarity with the chimeric RNA. (B) Chimeric RNAs act as scaffolds to bring two genomic loci into proximity, which might promote the breakage and fusion between the two gene loci. ss-splicing site.