Novel domain combinations in proteins encoded by chimeric transcripts

Abstract

Motivation: Chimeric RNA transcripts are generated by different mechanisms including pre-mRNA trans-splicing, chromosomal translocations and/or gene fusions. It was shown recently that at least some of chimeric transcripts can be translated into functional chimeric proteins.

Results: To gain a better understanding of the design principles underlying chimeric proteins, we have analyzed 7,424 chimeric RNAs from humans. We focused on the specific domains present in these proteins, comparing their permutations with those of known human proteins. Our method uses genomic alignments of the chimeras, identification of the gene-gene junction sites and prediction of the protein domains. We found that chimeras contain complete protein domains significantly more often than in random data sets. Specifically, we show that eight different types of domains are over-represented among all chimeras as well as in those chimeras confirmed by RNA-seq experiments. Moreover, we discovered that some chimeras potentially encode proteins with novel and unique domain combinations. Given the observed prevalence of entire protein domains in chimeras, we predict that certain putative chimeras that lack activation domains may actively compete with their parental proteins, thereby exerting dominant negative effects. More generally, the production of chimeric transcripts enables a combinatorial increase in the number of protein products available, which may disturb the function of parental genes and influence their protein-protein interaction network.

Availability: our scripts are available upon request.

Fig. 1.

A schematic representation of the chimera of TUFT1 and RNF115. This chimera is supported by two distinct ESTs (ESTid1 = ‘CB137847.1’ and ESTid2 = ‘CB137162.1’). The corresponding exon of TUFT1 incorporated in the chimera is depicted in blue and the exons of RNF115 are in brown

Fig. 2.

A schematic representation of the competition mechanism between the wild-type transcription factor (TF) and the dominant-negative chimera (DNC). (A). A lowly expressed DNC compete with TF. (B). As a result of the competition, the DNC binds a promoter region but cannot activate a target gene inserting dominant- negative effect.

Fig. 3.

Putative chimeric proteins can exert dominant negative effects. (A) Schematic view of transcription factor (TCF3) and ribosomal protein (RPS19). (B) The putative chimeric protein harnesses RPS19 to the DNA-binding domain of TCF3 and likely exerts a dominant negative effect by competing with wild type TCF3 for DNA binding. (C) Schematic view of guanine-monophosphate-synthetase (GMPS), which functions as a homodimer, and mixed-lineage leukemia (MLL). (D) The putative chimeric MLL/GMPS protein lacking a functional GMPS domain likely competes with parental GMPS to form dysfunctional heterodimers, impairing the biosynthesis regulated by GMPS