SUMO Pathway Modulation of Regulatory Protein Binding at the Ribosomal DNA Locus in Saccharomyces Cerevisiae

By Gillies, Jennifer; Hickey, Christopher M. et al. | Genetics, April 2016 | Go to article overview

SUMO Pathway Modulation of Regulatory Protein Binding at the Ribosomal DNA Locus in Saccharomyces Cerevisiae


Gillies, Jennifer, Hickey, Christopher M., Su, Dan, Wu, Zhiping, Peng, Junmin, Hochstrasser, Mark, Genetics


POST-TRANSLATIONAL protein modi fi cations provide a common mechanism for regulating protein-protein interactions, protein localization, and protein degradation. The small ubiquitin-related modifier (SUMO) protein family modifies target proteins through covalent attachment to lysine side chains (Johnson 2004). The function of substrate "sumoylation" varies with the protein that is sumoylated, but a common role is to modulate the assembly of large protein complexes either by creating additional binding sites or by blocking existing sites (Kerscher 2007).

Protein sumoylation occurs through an enzymatic cascade similar to ubiquitylation (Johnson 2004). In Saccharomyces cerevisiae, a single gene, SMT3, codes for SUMO, and as in most species, SUMO ligation is essential for viability. Removal of SUMO from target proteins is also an important regulatory step. S. cerevisiae has two SUMO proteases, Ulp1 and Ulp2 (Hickey et al. 2012). Most Ulp1 is bound to the nuclear pore complex (NPC), and the enzyme is essential for cell-cycle progression. NPC tethering regulates Ulp1 activity by restricting its access to sumoylated proteins (Li and Hochstrasser 2003; Panse et al. 2003). Ulp1 also processes the SUMO precursor by removing its last three residues, thereby exposing the C-terminal Gly-Gly motif required for SUMO conjugation. Ulp1 is essential for growth even if cells are provided with mature SUMO, indicating a critical function for its protein desumoylation activity.

Ulp2 is less active than Ulp1 in vitro and is not required for viability, although cells lacking Ulp2 are growth defective and sensitive to a wide range of stresses. Ulp2 localizes throughout the nucleus, with a slight concentration in the nucleolus (Srikumar et al. 2013b). It has long, poorly conserved regions flanking the catalytic domain, which are of ill-defined function other than a pair of nuclear-localization signals (NLSs) in the N-terminal domain (Kroetz et al. 2009). Large amounts of high molecular weight (HMW) SUMO conjugates, which accumulate in the stacker of SDS-PAGE gels, are observed in ulp2D cells. Correspondingly, Ulp2 has a preference in vitro for cleaving between SUMO monomers in polySUMO chains (Hickey et al. 2012; Eckhoff and Dohmen 2015). The identities of most of the HMW-SUMO conjugates are unknown, as is their contribution to the growth defects of ulp2D cells (Bylebyl et al. 2003).

Slx5/Slx8 is a heterodimeric ubiquitin ligase (E3) that can recognize SUMO-protein conjugates and is therefore referred to as a SUMO-targeted ubiquitin ligase (STUbL) (Prudden et al. 2007; Sun et al. 2007; Uzunova et al. 2007; Xie et al. 2010). The Slx5 subunit interacts directly with SUMO and polySUMO chains through four tandem SUMO-interacting motifs (SIMs). Slx8 has a single apparent SIM (Uzunova et al. 2007; Xie et al. 2007; Mullen and Brill 2008). Deleting the SLX5 gene suppresses ulp2D defects but exacerbates those of the ulp1ts mutant, consistent with distinct cellular roles of the two SUMO proteases (Xie et al. 2007; Mullen et al. 2011). Slx5/Slx8 has multiple functions and targets [not all requiring prior SUMO ligation (Xie et al. 2010)], including roles in DNA replication and repair (Burgess et al. 2007). The STUbL localizes at various sites within the nucleus as well, such as DNA replication forks and the NPC (Torres-Rosell et al. 2007; Nagai et al. 2008; Cook et al. 2009).

The SUMO pathway has been linked to the nucleolus, the cellular hub for the initial stages of ribosome assembly (Strunnikov et al. 2001; D'Amours et al. 2004; Panse et al. 2006; Takahashi et al. 2008; Srikumar et al. 2013b). To maintain robust ribosome production, cells have numerous ribosomal DNA (rDNA) copies, even though repeated DNA is prone to aberrant homologous recombination. S. cerevisiae has between 100 and 200 copies of the rDNA repeat, which consists of the 35S precursor rRNA gene, the 5S rRNA gene, and two nontranscribed spacers (Straight et al. 1999). Excessive homologous recombination of the rDNA leads to an increased number of rDNA repeats, which can produce extrachromosomal rDNA circles, potentially promoting senescence (Sinclair and Guarente 1997). …

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