Abstract
Using TSG101 pre-mRNA, we previously discovered cancer-specific re-splicing of mature mRNA that generates aberrant transcripts/proteins. The fact that mRNA is aberrantly re-spliced in various cancer cells implies there must be an important mechanism to prevent deleterious re-splicing on the spliced mRNA in normal cells. We thus postulated that mRNA re-splicing is controlled by specific repressors, and we searched for repressor candidates by siRNA-based screening for mRNA re-splicing activity. We found that knock-down of EIF4A3, which is a core component of the exon junction complex (EJC), significantly promoted mRNA re-splicing. Remarkably, we could recapitulate cancer-specific mRNA re-splicing in normal cells by knock-down of any of the core EJC proteins, EIF4A3, MAGOH, or RBM8A (Y14), implicating the EJC core as the repressor of mRNA re-splicing often observed in cancer cells. We propose that the EJC core is a critical mRNA quality control factor to prevent over-splicing of mature mRNA.
Highlights
The basic mechanism of how pre-mRNA splicing is initiated and proceeded has been characterized in detail, it is less well known how splicing is terminated
Our results indicate that EIF4A3 is a potent repressor of mRNA
Similar to EIF4A3, we found that knock-down of both MAGOH and RBM8A markedly activated the aberrant re-splicing of TSG101 mRNA, whereas the CASC3 knock-down had no effect (Figure 1c)
Summary
The basic mechanism of how pre-mRNA splicing is initiated and proceeded has been characterized in detail, it is less well known how splicing is terminated. Cis-acting splicing signals, such as 50 /30 splice sites and branch sites followed by a poly-pyrimidine tract, are not highly conserved; they are necessary but not sufficient to be utilized (reviewed in [1]). Because of this redundancy, there remain many splice site-like sequences in fully spliced mRNA. There remain many splice site-like sequences in fully spliced mRNA These spurious splice sites are usually never used, and the mature mRNA is safely exported to the cytoplasm for translation. The exact mechanism to control splicing termination is poorly understood We address this thorny problem by taking advantage of aberrant multi-step splicing. A normally spliced mRNA can be a substrate for further splicing, often in cancer cells, which is termed cancer-specific mRNA re-splicing
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