G3BP and its Binding Partners in Stress and Senescence

Abstract

Ageing is a process from which there is no escape, yet an understanding of the molecular mechanisms which underly this physiological deterioration, although the centre of a large deal of research, remains relatively elusive. Cytoplasmic stress granules are impermanent membrane-less intracellular organelles that exist transiently to aid the cell to overcome a period of stress, such as oxidative attack. The role these granules may play in ageing and senescence is not clear, although it is published that cells lose their ability to form such granules due to a loss of fundamental nucleating proteins, such as G3BP1 and TIAR, with age We investigate the interactions between stress granules and senescence by utilising a range of CRISPR-Cas9 mutant cell lines to begin to dissect their contribution to the senescence programme, presenting considerable evidence that loss of these nucleating proteins is not a universal mechanism through which granule assembly may be lost. We present a model of induced premature senescence using etoposide, doxorubicin, and the novel inducer Sin-1 and demonstrate that granule loss is complex and context-dependant. Our data generates new insight into granule dynamics in ageing, and describes a number of novel hypotheses for the loss of granules in senescence.