A Comparative Analysis of Stress Granule Assembly in Replicative and Stress-Induced Premature Senescence

Abstract

It has been well-established that primary human cells possess a limited proliferative capacity, undergoing an irreversible cell cycle arrest after a set number of population doublings known as replicative senescence. However, other senescence programmes can also be activated following exposure of cells to subcytotoxic oxidative stress and genotoxic stresses such as ionising radiation. Senescent cells have been linked through a multitude of studies to organismal ageing, and the dysfunction of these senescent cells can negatively affect tissue function through extracellular matrix remodelling and inflammatory protein secretion, resulting in the onset of a number of age-related diseases. Furthermore, it has been previously proposed that this release of inflammatory proteins, termed the Senescence-Associated Secretory Phenotype, may be exacerbated by aberrations in the cellular stress response.
The formation of cytoplasmic aggregates of RNA-binding proteins known as stress granules, which repress translation and modulate signalling pathways to promote cell survival, is a widely established response to cell stress. Stress granules are known to form more readily following stress in replicative senescent cells compared to in proliferating cells, but whether this is true of all senescence programmes remains unknown. Unexpectedly, this study demonstrates that prematurely senescent cells possess a far more limited granule-forming potential than both proliferating and replicative senescent cells, indicating that increased granule formation is not universal to all senescence phenotypes but differs between senescence programmes. In attempting to determine potential mechanisms through which this differential formation could be established it was further discovered that exposure of fibroblasts to X-ray irradiation did not induce the formation of stress granules, and that X-rays ablate the granule-forming capacity of these cells in the hours immediately following exposure. However, whist ultimately not conclusive, a subsequent investigation also suggested that the Wnt signalling pathway was likely not responsible for this loss of granule formation.
This study has therefore discovered two novel circumstances in which stress granule formation is inhibited. Whilst the mechanisms through which this abrogation of stress granule assembly is brought about remain unknown, both of these scenarios occurred following exposure to X-ray irradiation, both in the short- and long-term. Considering a common response to X-ray exposure is the activation of apoptosis, it is possible that stress granule ablation is a response intended to push cells towards cell death over survival. However, further mechanistic studies are required to better elucidate the signalling pathways responsible for this alteration of granule formation before the functional consequences of this granule inhibition can be fully determined.