Defining the spectrum of cellular protection against cadmium stress by Dsup expressed in yeast

Abstract The intrinsically disordered tardigrade Dsup protein has garnered attention for its ability to protect cells and organisms from radiation and oxidative stress. Our lab has previously described Dsup’s protective effect in yeast, finding that, while Dsup expression comes with a fitness cost, it improves survival under many stressors, including the heavy metal cadmium. While Dsup’s protection against oxidative stress and radiation is well-established, the mechanism by which it protects against other stressors is underinvestigated. To address this knowledge gap, we screened a collection of 4000 yeast deletion mutants expressing Dsup in the presence of three doses of cadmium to identify synergistic/synthetically lethal genes and processes. We find that Dsup broadly buffers many processes/genes at lower levels of cadmium stress but at higher doses, cells shift to buffering specific genes/processes. These results identify host genetic processes that influence Dsup’s ability to confer cadmium resistance to organisms. Article Summary Damage suppressor protein (Dsup) from extremophilic tardigrades protects against DNA damage when expressed, but how it protects against toxic metal stress is unclear. We screened 4,000 yeast deletion strains expressing Dsup at three doses of cadmium, a toxic heavy metal with deleterious biological and ecological effects. At low doses, Dsup buffered the loss of genes and processes while at higher doses buffering was restricted to specific genes. This shows genome-wide response to cadmium toxicity in yeast and identifies genes that interact with Dsup to confer protection. These observations highlight key affected processes and may inform efforts to engineer countermeasures.