Academic journal article Genetics

Mms21 SUMO Ligase Activity Promotes Nucleolar Function in Saccharomyces Cerevisiae

Academic journal article Genetics

Mms21 SUMO Ligase Activity Promotes Nucleolar Function in Saccharomyces Cerevisiae

Article excerpt

MMS21 is a SUMO ligase that is a subunit of the Smc5/6 complex. The Smc5/6 complex has been shown to regulate sister chromatid segregation, DNA replication, and DNA damage repair (Lindroos et al. 2006; Rai et al. 2011; Almedawar et al. 2012; McAleenan et al. 2012; Wu et al. 2012; Bermudez-Lopez et al. 2015). The structural maintenance of chromosome (SMC) complexes are conserved from prokaryotes to humans and they promote chromosome integrity. Previous reports have shown that Mms21 SUMO ligase activity is required for the Smc5/6 complex to function in those cellular processes (Zhao and Blobel 2005; Murray and Carr 2008; Takahashi et al. 2008; Potts 2009; Stephan et al. 2011; Bermudez-Lopez et al. 2015).

One of the striking phenotypes of loss of Mms21 sumoylation activity is an aberrant nucleolus (Zhao and Blobel 2005). The nucleolus is the nuclear body where ribosomal DNA (rDNA) resides and ribosomes begin to be assembled from their RNA and protein components. Mms21 has been shown to target some nucleolar proteins for sumoylation (Albuquerque et al. 2013). The Smc5/6 complex binds to the rDNA repeats, suggesting it could play a role in the formation of the nucleolus (Torres-Rosell et al. 2005b). Furthermore, the Smc5/6 complex is required for rDNA integrity (Torres-Rosell et al. 2005a) and segregation (Torres-Rosell et al. 2005b). The aberrant nucleolar structure observed in cohesin loss-of-function mutants was a harbinger of defects in ribosome biogenesis (Bose et al. 2012). Given the defect in nucleolar structure in MMS21 mutants, we speculated that the sumoylation activity of Mms21 might be required for nucleolar function.

Faithful regulation of ribosome biogenesis is important for translation and cell proliferation. In proliferating cells, there is a high demand for protein production. To meet this demand, cells must produce ribosomes at a rapid rate (Montanaro et al. 2008; Lempiainen and Shore 2009). Defects in ribosome biogenesis have been shown to correlate with reduced or altered protein translation and growth defects (Zanchin et al. 1997; Yamada et al. 2007; Jack et al. 2011; Bose et al. 2012; Xu et al. 2013). More importantly, deregulation of ribosome biogenesis has been correlated with tumorigenesis and developmental syndromes, including cohesinopathies and ribosomopathies (Montanaro et al. 2008; Ruggero 2013; Zakari et al. 2015), demonstrating that proper ribosome biogenesis is critical for human health.

Ribosome biogenesis requires the assembly and transport of many different RNA and protein components. This process includes ribosomal RNA (rRNA) transcription, processing, ribosome assembly, and export. The budding yeast 35S rRNA precursor is transcribed by RNA polymerase I in the nucleolus and undergoes a series of cleavages and modifications to generate the 25S, 18S, and 5.8S rRNAs. The 25S, 5.8S, and 5S (transcribed by RNApolymerase III) rRNAs and the 18S rRNA assemble the 60S and the 40S preribosome particles, respectively, with both large and small ribosomal proteins and transacting factors (Strunk and Karbstein 2009; Kressler et al. 2010; Woolford and Baserga 2013). After assembly of the preribosome particles, the 60S and the 40S preribosome particles undergo maturation and are exported to the cytoplasm to form functional ribosomes.

We find that mutations in the Smc5/6 complex allow ribosomal proteins to accumulate in the nucleus. In addition, rRNA is produced at a reduced rate and translational stress is detected in the mms21R!NGA mutant. The gene expression profile in the mms21RlNGD mutant is consistent with the idea that translation could be negatively affected. Deletion of RPL19A or the previously identified suppressor MPH1 partially rescues growth and the accumulation of ribosomal proteins in the nucleus. Deletion of the gene encoding the Mph1 helicase also partially rescues rRNA production and translational stress in the mms21RlNGD mutant. Our study suggests that the Smc5/6 complex supports nucleolar function. …

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