An Exploration of Stress, Signaling, and Ubiquitin-like Modifiers

Abstract

Cells face a barrage of internal and external stresses that could inflict severe damage on the molecules essential for life. To cope with environmental challenges, cells have evolved complex stress responses. Posttranslational protein modifications, including ubiquitin-like modifiers, are a major means by through which cells respond to these changing environmental conditions. This thesis explores how the small ubiquitin-like modifier (SUMO) is used to modulate cellular outcomes via transcription, with a particular focus on cellular contexts that require rapid transcriptional changes, such as stress. I present evidence from studies in Saccharomyces cerevisiae that SUMO can be inhibitory to transcription both through direct signaling and non-signaling modes of function. First, I present my findings that SUMO can act as a signal to inhibit the transcription activation potential of a predicted SUMO-targeted ubiquitin ligase that also functions in transcriptional silencing. I discuss potential models for how SUMO might direct switching between transcriptional silencing and activation functions of this protein. Second, discuss independent work demonstrating that SUMO, a highly soluble protein, can promote transcriptional repression in a non-signaling manner by solubilizing transcriptional regulators at risk of misfolding during stress. I show that during hyperosmotic stress, two members of a transcriptional corepressor complex are rapidly and transiently SUMO-modified, and loss of this sumoylation drives accumulation of these proteins into inclusions and correlates with widespread loss of transcriptional repression. Finally, I discuss the broader implications of the signaling and non-signaling functions of SUMO in transcriptional modulation, with a focus on SUMO's potential to drive the adaptive potential of cells in changing environmental contexts.