A lysine desert protects a novel domain in the slx5-slx8 sumo targeted ub ligase to maintain sumoylation levels in saccharomyces cerevisiae

Pragati Sharma, Janet R. Mullen, Minxing Li, Mikel Zaratiegui, Samuel F. Bunting, Steven J. Brill

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Protein modification by the small ubiquitin-like modifier (SUMO) plays important roles in genome maintenance. In Saccharomyces cerevisiae, proper regulation of sumoylation is known to be essential for viability in certain DNA repair mutants. Here, we find the opposite result; proper regulation of sumoylation is lethal in certain DNA repair mutants. Yeast cells lacking the repair factors TDP1 and WSS1 are synthetically lethal due to their redundant roles in removing Top1-DNA covalent complexes (Top1ccs). A screen for suppressors of tdp1Δ wss1Δ synthetic lethality isolated mutations in genes known to control global sumoylation levels including ULP1, ULP2, SIZ2, and SLX5. The results suggest that alternative pathways of repair become available when sumoylation levels are altered. Curiously, both suppressor mutations that were isolated in the Slx5 subunit of the SUMO-targeted Ub ligase created new lysine residues. These “slx5-K” mutations localize to a 398 amino acid domain that is completely free of lysine, and they result in the auto-ubiquitination and partial proteolysis of Slx5. The decrease in Slx5-K protein leads to the accumulation of high molecular weight SUMO conjugates, and the residual Ub ligase activity is needed to suppress inviability presumably by targeting polysumoylated Top1ccs. This “lysine desert” is found in the subset of large fungal Slx5 proteins, but not its smaller orthologs such as RNF4. The lysine desert solves a problem that Ub ligases encounter when evolving novel functional domains.

Original languageEnglish (US)
Pages (from-to)1807-1821
Number of pages15
JournalGenetics
Volume206
Issue number4
DOIs
StatePublished - 2017

All Science Journal Classification (ASJC) codes

  • Genetics

Keywords

  • SLX5-SLX8
  • SUMO
  • SUMO-targeted Ub ligase
  • Smt3
  • Synthetic lethality

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