| Summary: | (1) Background: Numerous prions exist in the budding yeast, including [<i>SWI</i><sup>+</sup>], the prion form of Swi1—a subunit of the chromatin-remodeling complex SWI/SNF. Despite decades of research, the molecular mechanisms underlying prion initiation and propagation are not fully understood. In this study, we aimed to identify endogenous cellular proteins that destabilize [<i>SWI</i><sup>+</sup>]. (2) Methods: We screened the MoBY-ORF 2.0 library for proteins that destabilize [<i>SWI</i><sup>+</sup>] upon overproduction. We further explored the effects of the identified candidates against other yeast prions and analyzed their potential prion-curing mechanisms. (3) Results: Eighty-two [<i>SWI</i><sup>+</sup>] suppressors were identified, and their effects were shown to be [<i>SWI</i><sup>+</sup>]-specific. Interestingly, a few documented [<i>SWI</i><sup>+</sup>] suppressors were not among the identified hits. Further experiments indicate that, for some of these [<i>SWI</i><sup>+</sup>] suppressors, their overproduction, and thus their prion-curing activities, are regulated by environmental conditions. Bioinformatics analyses show that our identified [<i>SWI</i><sup>+</sup>] suppressors are involved in diverse biological functions, with gene ontology term enrichments specifically for transcriptional regulation and translation. Competition for Swi1 monomers between [<i>SWI</i><sup>+</sup>] and Swi1 interactors, including the SWI/SNF complex, is a potential prion-curing mechanism. (4) Conclusions: We identified a number of [<i>SWI</i><sup>+</sup>]-specific suppressors that highlight unique features of [<i>SWI</i><sup>+</sup>] in maintaining its self-perpetuating conformations.
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