Toward a Deeper Understanding and Appreciation of Stress-Induced Biomolecular Condensation

When cells experience stress, they undergo a number of dramatic intracellular molecular changes. One of these changes is the formation of biomolecular condensates, or clusters of mRNA and proteins. When these clusters are visible by microscopy, they are called "stress granules." Although these condensates have been observed for many years across many species, many questions remain. What exactly is the composition of a stress granule? What is the mechanism of formation? What, if any, is the function of stress granules? Are they an adaptive response by the cell? The field has not coalesced around answers to these fundamental questions, compelling further study.

This dissertation covers a review of stress granules, summarizing previous work and outlining the grand challenges in this area. Additionally, it includes a project on the stress-induced condensation of mRNA. During stress in yeast, we observed global, length-independent condensation of mRNA that seems to be regulated by a block in translation initiation. We also observed that stress-induced transcripts are excluded from condensates, driven by the timing of transcription. Finally, our data suggest the existence of small, submicroscopic condensates that are not visible by standard microscopy. We propose a model where stress-induced mRNA condensation allows the cell to prioritize translation during stress, sequestering away old transcripts so the cell can focus on a stress-specific translational program. Lastly, this work includes a study on whether the stress-induced condensation behavior of poly-A binding protein 1 (Pab1) regulates the translation of stress transcripts during recovery from stress. We did not find data to support this model, leaving Pab1's adaptive condensation behavior as an open question.

As a whole, this work comments broadly on stress granules and specifically on how condensation does and does not contribute to the stress response in yeast. It also points toward future challenges and goals, such as a deeper understanding of the mechanism of mRNA condensation and its precise adaptive role during stress.