The journey of a precursor messenger RNA (pre-mRNA) from the nucleus to the cytoplasm, up to its eventual interaction with ribosomes, involves numerous tightly controlled steps. Improperly matured RNAs must be eliminated in the cell, and the nonsense-mediated mRNA decay (NMD) pathway degrades any imperfect mRNAs. Here, the exon junction complex (EJC) enhances the degradation efficiency of the NMD and is also thought to contribute to the export of spliced mRNAs into the cytoplasm. In their study on p. 1519, Maria Carmo-Fonseca and co-workers investigate the effect of the pharmacological splicing inhibitors spliceostatin A, meayamycin and pladienolide B, potentially potent anti-tumour compounds, on mRNA processing. As expected, the inhibition of splicing leads to an accumulation of unspliced pre-mRNAs in the nucleus. Interestingly, a small proportion of pre-mRNAs were nevertheless exported to the cytoplasm in a manner that is dependent on the transcription-export complex component ALYREF. The authors show that intron-containing transcripts associate with ALYREF, but not an EJC core protein, whereas cytoplasmic unspliced pre-mRNAs are degraded by the NMD. Thus, this study not only shows that cytoplasmic pre-mRNAs evoke an EJC-independent NMD pathway response when splicing is blocked, but also provides insights into the effects of a set of potential anti-cancer drugs on the stability and transport of mRNAs.
