The small ubiquitin-like modifier SUMO regulates many aspects of cellular physiology to maintain cell homeostasis, both under normal conditions and during cell stress. Components of the transcriptional apparatus and chromatin are among the most prominent SUMO substrates. The prevailing view is that SUMO serves to repress transcription. However, as we will discuss in this review, this model needs to be refined, because recent studies have revealed that SUMO can also have profound positive effects on transcription.
Transcription factors are abundant Sumo targets, yet the global distribution of Sumo along the chromatin and its physiological relevance in transcription are poorly understood. Using Saccharomyces cerevisiae, we determined the genome-wide localization of Sumo along the chromatin. We discovered that Sumo-enriched genes are almost exclusively involved in translation, such as tRNA genes and ribosomal protein genes (RPGs). Genome-wide expression analysis showed that Sumo positively regulates their transcription. We also discovered that the Sumo consensus motif at RPG promoters is identical to the DNA binding motif of the transcription factor Rap1. We demonstrate that Rap1 is a molecular target of Sumo and that sumoylation of Rap1 is important for cell viability. Furthermore, Rap1 sumoylation promotes recruitment of the basal transcription machinery, and sumoylation of Rap1 cooperates with the target of rapamycin kinase complex 1 (TORC1) pathway to promote RPG transcription. Strikingly, our data reveal that sumoylation of Rap1 functions in a homeostatic feedback loop that sustains RPG transcription during translational stress. Taken together, Sumo regulates the cellular translational capacity by promoting transcription of tRNA genes and RPGs.
Maintaining cellular homeostasis under changing nutrient conditions is essential for the growth and development of all organisms. The mechanisms that maintain homeostasis upon loss of nutrient supply are not well understood. By mapping the SUMO proteome in Saccharomyces cerevisiae, we discovered a specific set of differentially sumoylated proteins mainly involved in transcription. RNA polymerase III (RNAPIII) components, including Rpc53, Rpc82, and Ret1, are particularly prominent nutrient-dependent SUMO targets. Nitrogen starvation, as well as direct inhibition of the master nutrient response regulator target of rapamycin complex 1 (TORC1), results in rapid desumoylation of these proteins, which is reflected by loss of SUMO at tRNA genes. TORC1-dependent sumoylation of Rpc82 in particular is required for robust tRNA transcription. Mechanistically, sumoylation of Rpc82 is important for assembly of the RNAPIII holoenzyme and recruitment of Rpc82 to tRNA genes. In conclusion, our data show that TORC1-dependent sumoylation of Rpc82 bolsters the transcriptional capacity of RNAPIII under optimal growth conditions.I n yeast and in more complex eukaryotes, cell growth is restricted by the rate of mRNA translation and ribosome biogenesis, which depend on the transcription of ribosomal protein genes (RPGs), tRNAs and rRNAs. Synthesis of rRNA, tRNAs, and 5S rRNA represents 75% of total cellular transcription, whereas transcription of RPGs corresponds to 50% of RNA polymerase II (RNAPII) initiation events (1). These processes consume a significant portion of the cell's resources, making nutrient availability a limiting factor to cell growth and proliferation (2). The conserved rapamycin-sensitive target of rapamycin complex 1 (TORC1) is a master regulator of the cellular nutrient response (2, 3). Under nitrogen-rich conditions, TORC1 promotes growth-related processes, like protein synthesis, ribosome biogenesis, and tRNA synthesis, while inhibiting catabolic processes, like autophagy (2). Conversely, inhibition of TORC1 activity by nitrogen depletion (or addition of the TORC1 inhibitor rapamycin) results in a metabolic switch from anabolism to catabolism, which involves many cellular processes, including down-regulation of transcription of RPGs, rRNA and tRNA genes (2, 3).A key downstream target of TORC1 in regulation of tRNA transcription is the conserved RNAPIII inhibitor Maf1, which is phosphorylated and maintained in the cytoplasm under nitrogenrich conditions (2, 3). Maf1 becomes hypophosphorylated under conditions that inhibit TORC1, allowing it to enter the nucleus where it associates with TFIIIB. The interaction between Maf1 and TFIIIB prevents the recruitment of RNAPIII and precludes transcription reinitiation at 5S rRNA and tRNA genes (4, 5). However, expression of an unphosphorylatable maf1 mutant does not completely repress tRNA expression in nutrient-replete cells (6), suggesting that dephosphorylation of Maf1 alone is not sufficient to fully inhibit RNAPIII. Indeed, inhibition of TORC1 also results in phospho...
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