Regulated pre-mRNA splicing: the ghostwriter of the eukaryotic genome

Abstract

Intron removal is at the heart of mRNA synthesis. It is mediated by one of the cell's largest complexes, the spliceosome. Yet, the fundamental chemistry involved is simple. In this review we will address how the spliceosome acts in diverse ways to optimize gene expression in order to meet the cell's needs. This is done largely by regulating the splicing of key transcripts encoding products that control gene expression pathways. This widespread role is evident even in the yeast Saccharomyces cerevisiae, where many introns appear to have been lost; yet how this control is being achieved is known only in a few cases. Here we explore the relevant examples and posit hypotheses whereby regulated splicing fine-tunes gene expression pathways to maintain cell homeostasis. This article is part of a Special Issue entitled: Nuclear Transport and RNA Processing.

Figure 1

Pre-mRNA splicing can fine-tune several different gene expression reactions via splicing sensitive regulators, including RNP biogenesis and transport, ribosome biogenesis and function, or transcription itself. The factors shown in the ovals undergo regulated splicing to affect the processes shown in the boxes. It is likely that others are still unknown. Nevertheless, those indicated provide a paradigm for regulatory strategies centered on the control of pre-mRNA splicing.

Figure 2

Splicing regulation of the RPL30 transcript. The RPL30 gene encodes the essential protein L30. Pre-mRNA splicing contributes to maintaining the protein levels by an autoregulatory feedback loop. The newly made L30 (shown as a ball) must be transported to the nucleolus to join ribosome biosynthesis (top). However, if that is not possible (conditions of excess L30), the protein binds its own pre-mRNA. This prevents RPL30 splicing and triggers the transport and decay of the pre-mRNA in the cytoplasm. The choice for L30 between either ribosome biosynthesis or splicing control (orange square) has been depicted in the nucleus, but its mechanism and location is unknown (for simplicity reasons the binding site of L30 is shown entirely in exon 1, although it includes the 5' ss).

Figure 3

Regulated splicing of SUS1 fine-tunes RNA export and histone H2B ubiquitination. Under unstressed conditions (Left side of figure) SUS1 pre-mRNA undergoes splicing and is exported to allow production of Sus1 protein that can either participate in histone H2B deubiquitination as part of the SAGA complex (top) or can associate with the TREX-2 proteins at the nuclear pore (Shown in dark blue). Intron 1 is retained in a small fraction of the RNAs and is either targeted to NMD or may make a truncated product. Under stress conditions, intron 1retention is enhanced. However, it is unclear how much of this product is targeted to NMD vs. translation of a truncated product. It is possible that the truncated protein can associate with either the TREX-2 complex or with SAGA (indicated by “?”). Sgf11 is destabilized by the lack of Sus1 [81], so it has been left off out of the SAGA complex that contains less SUS1. It is also possible that Sus1, via its H2B ubiquitination activity or by interacting with the splicing (not shown), may influence its own splicing (Dotted arrow).