Distinct adaptive mechanisms drive recovery from aneuploidy caused by loss of the Ulp2 SUMO protease

Abstract

In response to acute loss of the Ulp2 SUMO-specific protease, yeast become disomic for chromosome I (ChrI) and ChrXII. Here we report that ChrI disomy, which creates an adaptive advantage in part by increasing the dosage of the Ccr4 deadenylase, was eliminated by extended passaging. Loss of aneuploidy is often accompanied by mutations in essential SUMO-ligating enzymes, which reduced polySUMO-conjugate accumulation. The mRNA levels for almost all ribosomal proteins increase transiently upon initial loss of Ulp2, but elevated Ccr4 levels limit excess ribosome formation. Notably, extended passaging leads to increased levels of many small nucleolar RNAs (snoRNAs) involved in ribosome biogenesis, and higher dosage of three linked ChrXII snoRNA genes suppressed ChrXII disomy in ulp2Δ cells. Our data reveal that aneuploidy allows rapid adaptation to Ulp2 loss, but long-term adaptation restores euploidy. Cellular evolution restores homeostasis through countervailing mutations in SUMO-modification pathways and regulatory shifts in ribosome biogenesis.

The Ulp2 SUMO protease promotes transcription elongation through regulation of histone sumoylation

“…To map Ulp2 binding sites on a genome-wide scale, we carried out ChIP-seq experiments ( Fig 1G) and compared genome-wide association of Ulp2 with the RNA-seq data in Fig 1B. Consistent with our previous report (Ryu et al, 2018), we found that Ulp2 was enriched at most ribosomal protein gene loci. Furthermore, we observed a greater percentage of genes that were highly expressed associated with Ulp2, consistent with a potential role for Ulp2 in transcription.…”

“…Furthermore, we observed a greater percentage of genes that were highly expressed associated with Ulp2, consistent with a potential role for Ulp2 in transcription. Although Ulp2 has previously been shown to associate specifically with rDNA, RP, and snoRNA genes (Liang et al, 2017;Ryu et al, 2018), these observations provide the first direct evidence for the transcription-linked association of Ulp2 with actively transcribed genes in vivo. Although Ulp2 has previously been shown to associate specifically with rDNA, RP, and snoRNA genes (Liang et al, 2017;Ryu et al, 2018), these observations provide the first direct evidence for the transcription-linked association of Ulp2 with actively transcribed genes in vivo.…”

“…To investigate this further, we first grouped previously published RNAseq data comparing wild-type (WT) and ulp2D strains (Ryu et al, 2018) into three categories: high, medium, or low expression levels ( Fig 1A and B). To investigate this further, we first grouped previously published RNAseq data comparing wild-type (WT) and ulp2D strains (Ryu et al, 2018) into three categories: high, medium, or low expression levels ( Fig 1A and B).…”

“…A Transcriptome re-analysis of ulp2D strains compared with WT (MHY1379) from previous RNA-seq experiments (Ryu et al, 2018). Two-dimensional agglomerative hierarchical clustering shows 2,903 significantly up-or down-regulated genes (P < 0.05) in triplicate RNA samples.…”

“…Interestingly, SUMO plays an important role not only in transcriptional activation by the Gcn4 transcription factor but also in subsequent transcriptional deactivation through a combination of SUMO-dependent clearance of Gcn4 and stabilization of Tup1 corepressor binding at promoters (Ng et al, 2015). Ulp1 localized at nuclear pore complexes accelerates GAL1 de-repression kinetics (Texari et al, 2013), while association of Ulp2 with RP and snoRNA genes limits accumulation of SUMO at these loci (Ryu et al, 2018). Ulp1 localized at nuclear pore complexes accelerates GAL1 de-repression kinetics (Texari et al, 2013), while association of Ulp2 with RP and snoRNA genes limits accumulation of SUMO at these loci (Ryu et al, 2018).…”