SUMO and cellular adaptive mechanisms

Abstract

Stress response: how cells wrestle with SUMO disruption Cellular stress caused by disrupting attachment of the ubiquitous small ubiquitin-like modifier (SUMO) proteins, which are present in most organisms and regulate numerous DNA processes and stress responses by attaching to key proteins, results in some remarkable adaptations. Mark Hochstrasser at Yale University, New Haven, USA, and co-workers review how this "sumoylation" is reversed by protease enzymes, and how imbalances between sumoylation and desumoylation may be linked to diseases including cancer. When certain SUMO proteases are deliberately disrupted, the cells quickly become aneuploid, i.e., carry an abnormal number of chromosomes. These cells show severe growth defects, but over many generations they regain the normal number of chromosomes. They also undergo genetic changes that promote alternative mechanisms that compensate for losing the SUMO protease and facilitate the same efficient stress responses as the original cells.

The ubiquitin family member SUMO is a covalent regulator of proteins that functions in response to various stresses, and defects in SUMO-protein conjugation or deconjugation have been implicated in multiple diseases. The loss of the Ulp2 SUMO protease, which reverses SUMO-protein modifications, in the model eukaryoteSaccharomyces cerevisiaeis severely detrimental to cell fitness and has emerged as a useful model for studying how cells adapt to SUMO system dysfunction. Both short-term and long-term adaptive mechanisms are triggered depending on the length of time cells spend without this SUMO chain-cleaving enzyme. Such short-term adaptations include a highly specific multichromosome aneuploidy and large changes in ribosomal gene transcription. While aneuploidulp2 Delta cells survive, they suffer severe defects in growth and stress resistance. Over many generations, euploidy is restored, transcriptional programs are adjusted, and specific genetic changes that compensate for the loss of the SUMO protease are observed. These long-term adapted cells grow at normal rates with no detectable defects in stress resistance. In this review, we examine the connections between SUMO and cellular adaptive mechanisms more broadly.