The present GEITP topic here is something that might revolutionize our thinking about RNA processing in all eukaryotes (i.e. organisms such as yeast or human having chromosomal pairs, as opposed to prokaryotes such as bacteria that have single unpaired chromosomes). RNA molecules that are newly transcribed from DNA — contain intron and exon sequences. Introns are excised by means of a process called “RNA splicing”, during which the remaining exon sequences are joined together (ligated) to form mature messenger RNA (mRNA), which is then translated into protein. RNA splicing releases a lariat-shaped intron that is rapidly converted (debranched) to a linear form, and then degraded. Much of what we know about the molecular machinery — the spliceosome and its associated factors — and the mechanisms of splicing has come from genetic and biochemical experiments using baker’s yeast (Saccharomyces cerevisiae).
Many studies have suggested that most yeast introns can be removed with little consequence for the cell. Two articles [see attached] now challenge this view — by showing that introns help yeast cells in culture to sense a lack of essential nutrients in their growth medium and to adjust the rate of cell growth to adapt to this change in environment. Although the splicing machinery has been highly conserved during evolution, we must keep in mind that gene architecture is complex and varies across organisms.
However, the yeast genome is highly streamlined — in comparison with those of most other eukaryotes (i.e. the group of organisms that include plants, fungi and animals). Approximately 5% of protein-coding genes in yeast contain introns, and only nine genes contain more than one intron. By contrast, 90% of genes in mammals contain introns, with an average of eight introns per gene. In yeast, as in other organisms, “introns have been viewed as an dispensable by-product of exon ligation”, because of their rapid degradation after splicing.
Authors [see first article] systematically deleted all known introns in yeast genes. In most cases, cells with all introns deleted — growth was found to be impaired — when nutrients are depleted; this effect of introns on growth is not linked to expression of the host gene, and was reproduced even when translation of the host mRNA into protein was blocked. Authors found that introns promote resistance to starvation by enhancing the repression of ribosomal protein genes downstream of the nutrient-sensing TORC1 (yeast equivalent of the mammalian Target Of Rapamycin Complex-1, a protein complex that functions, also in mammals, as a nutrient/energy/redox sensor and controls protein synthesis) and PKA (protein kinase-A, which is mammals has functions such as regulation of glycogen, sugar, and lipid metabolism) pathways.
Authors [see 2nd article] excised 34 introns in yeast and found that — despite being rapidly degraded in log-phase growth — the introns accumulated as linear RNAs, under conditions of either saturated-growth, or other stresses that cause prolonged inhibition of TORC1. Introns that became stabilized — remained associated with components of the spliceosome, and differed from other spliceosomal introns in having a short distance between their lariat branch point and the 3′ splice site (which is necessary and sufficient for their stabilization).
Deletion of these introns is therefore disadvantageous in saturated conditions and causes aberrantly high growth rates in yeast that are chronically challenged with the TORC1 inhibitor (rapamycin). Re-introduction of native, or engineered, stable introns suppresses this aberrant rapamycin response. Thus, excised introns function within the TOR growth-signalling network of S. cerevisiae and, more generally, excised spliceosomal introns appear to have biological functions. Collectively, the data from both papers reveal functions for introns — which might help to explain their evolutionary preservation in genes, and the results uncover regulatory mechanisms of cell adaptations to starvation. Lastly, as is commonly the case, “if it happens in yeast, don’t be surprised if it also happens in mammals including humans.” )
DwN
Nature 31 Jan 2o19; 565: 606–611 & 612–617 [two articles] & 578-579 [editorial]