The finding that the Mediator protein complex contributes to messenger RNA export from the nucleus in yeast adds to a growing list of roles for the complex in regulating transcriptional processes.
Gene transcription is fundamental to all major physiological processes, and defects in its regulation underlie myriad human diseases. Transcription culminates in the export of messenger RNA transcripts from the nucleus to the cytoplasm, where they are translated into proteins. In a paper in Cell, Schneider et al.1 use a combination of structural and cell biology, biochemistry, yeast genetics and transcript analyses to describe how this process is regulated by cooperation between the mRNA export machinery and Mediator — a large, multi-subunit protein complex best known for regulating the activity of the enzyme RNA polymerase II (pol II) during the early stages of transcription2.
Many factors converge on nascent mRNA transcripts to facilitate their export from the nucleus. One such factor, the TREX-2 protein complex, regulates export through interactions with other complexes, including pol II and the nuclear pore complex (NPC)3, which acts as a gateway for cellular components to exit the nucleus and enter the cytoplasm. However, the mechanisms by which TREX-2 acts are uncertain.
Schneider et al. investigated TREX-2 in the brewer's yeast Saccharomyces cerevisiae. In yeast cells lacking the TREX-2 subunit Sac3, the composition of the Mediator complex changed. Specifically, components of the Mediator 'Cdk8 kinase' module failed to associate with the rest of the complex. The authors demonstrated that TREX-2 physically associates with Mediator, and that this association depends on Sac3 and a Mediator subunit implicated in the activation of transcription, Med31.
A series of experiments then showed a functional interdependence between Mediator and TREX-2. In yeast, genes that are in the process of being transcribed associate with the NPC, presumably to facilitate mRNA export to the cytoplasm4. Schneider and colleagues demonstrated that, like Sac3, Med31 is required for gene targeting to the NPC, implying that Mediator is involved in mRNA export (Fig. 1). However, in contrast to cells lacking Sac3, mRNA export seemed normal in cells lacking Med31 or the Cdk8 kinase protein. Thus, although the authors' data support a role for Mediator in mRNA export, the precise molecular mechanism remains unclear.
Messenger RNA export joins a long list of regulatory roles for Mediator. And Schneider and colleagues' work adds to a growing set of studies5,6,7 suggesting that Mediator regulates late stages of transcription, such as mRNA processing, in addition to its role in transcription initiation2.
Note, however, that indirect effects could also contribute to the mRNA export or gene–NPC association defects reported by the authors. Consistent with a previous study8, Schneider et al. found decreased expression of genes involved in the biosynthesis pathway of sulfur-containing amino-acid residues in cells lacking Sac3 or Med31. An end product of this pathway is S-adenosyl methionine (SAM), which is an essential cofactor for methyltransferase enzymes. A reduction in SAM levels would be expected to inhibit methyltransferase activity, which, in S. cerevisiae, regulates mRNA processing and export9,10.
An array of research avenues opens up from Schneider and colleagues' study. For example, the relevance of these yeast findings to human Mediator remains to be determined. Although the authors demonstrated that TREX-2 interacts with Mediator in S. cerevisiae, existing studies of human Mediator-interacting proteins are largely devoid of human versions of the TREX-2 subunits. The functional link between S. cerevisiae Mediator and mRNA export will probably be evolutionarily conserved in some way, but the mechanisms by which the protein complex acts in human cells are likely to be distinct. Most S. cerevisiae mRNAs are not spliced into different versions of the transcript, for instance, in contrast to human mRNAs. Active genes in human cells do not typically associate with the nuclear periphery or the NPC, unlike genes in yeast. Instead, data suggest11 that active genes are found in the nuclear interior in human cells, and that they preferentially associate with structures called PML nuclear bodies, or with 'mobile' NPC proteins such as NUP98 (ref. 4).
An intriguing implication of the current study is the potential involvement of Mediator in regulating transcriptional memory, in which reactivation of specific genes, such as those induced by stress, occurs faster in progeny cells whose parents have previously experienced that stress4. This behaviour has been demonstrated in both yeast and mammalian cells4, although the underlying mechanisms are incompletely understood. In S. cerevisiae, maintenance of gene–NPC associations following cell division correlates with maintenance of transcriptional memory4. Schneider et al. showed that gene–NPC association requires Med31, suggesting a potential role for Mediator in this process.
An interesting aspect of transcriptional memory in yeast is its apparent dependence on a looped genomic DNA architecture that juxtaposes the gene's 5′ end (the start site for transcription) and 3′ end (the site of transcriptional termination)12. Although DNA architecture at active genes is different in humans, it is noteworthy that Mediator seems to be involved in the formation and stabilization of these loops in both species7,13 (Fig. 1). It will be interesting to see whether Mediator, perhaps through its Med31 subunit, contributes to such epigenetic mechanisms of transcriptional memory. For these and other reasons, Schneider and colleagues' study represents an important advance, with mechanistic implications that remain to be explored.
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