Stress resistance and the essential iron-sulphur cluster protein Rli1

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An inherent feature of life is that organisms must cope with various forms of environmental stress. For aerobic organisms which live in an oxygenated environment, e.g. humans, oxygen itself imposes a stress as it is the source of reactive oxygen species (ROS). ROS are highly damaging to the major components of cells. Among the most ROS-sensitive molecules of cells are components of certain proteins, termed iron-sulphur (FeS) clusters. Because of their oxygen sensitivity, these FeS clusters are considered a major limitation for successful aerobic existence. Nevertheless FeS clusters are essential, and that essentiality appears to rest on the requirement organisms have for the FeS protein Rli1p. Rli1p is essential to organisms because it is required for the process of protein synthesis. It may be no coincidence that, through evolution, Rli1p has been one of the most highly conserved proteins in biology. This conservation is helpful because it means that Rli1p function can be explored in relatively simple model organisms like yeast, which is very easy to grow in the lab and to manipulate for experiments. Conveniently, yeast has also proven an ideal model for studies of stress responses in cells, having yielded a range of key insights over recent years relevant to disease processes in humans and to the biotechnological applications of microorganisms. With the yeast model, we recently discovered a novel cellular function that helps to preserve the integrity of FeS clusters during stress. That work gave new insight to how organisms cope with an aerobic lifestyle. Moreover, in related experiments, we obtained the first experimental evidence that Rli1p is a key factor determining the stress resistance of cells. This research proposal is centered on that exciting discovery, supported by our preliminary data. Specifically, we will test the hypothesis that its FeS clusters make Rli1p a target of a number of major stressors, and that the essentiality of Rli1p means that such targeting is a cause of cell death during stress. The work programme will involve both screening approaches and specific manipulations to test the hypothesis. We will examine Rli1p function over a wide range of stress conditions. We will also exploit the power of yeast genetics to identify cellular factors that impact Rli1p function during stress. In addition, we will elucidate the mechanism(s) of Rli1p targeting. These studies are important as Rli1p has not been examined previously in this context, yet the evidence we discuss indicate that Rli1p is likely to be a major player in determining the abilities of organisms to cope with certain stresses. Elucidation of that role is vital if this research may be exploited for improving biotechnological processes or health in the future.