Two cytoplasmically inherited determinants related by their manifestation to the control of translation accuracy were previously described in yeast. Cells carrying one of them, [PSI+], display a nonsense suppressor phenotype and contain a prion form of the Sup35 protein. Another element, [PIN+], determines the probability of de novo generation of [PSI+] and results from a prion form of several proteins, which can be functionally unrelated to Sup35p. Here we describe a novel nonchromosomal determinant related to the SUP35 gene. This determinant, designated [ISP+], was identified as an antisuppressor of certain sup35 mutations. We observed its loss upon growth on guanidine hydrochloride and subsequent spontaneous reappearance with high frequency. The reversible curability of [ISP+] resembles the behavior of yeast prions. However, in contrast to known prions, [ISP+] does not depend on the chaperone protein Hsp104. Though manifestation of both [ISP+] and [PSI+] is related to the SUP35 gene, the maintenance of [ISP+] does not depend on the prionogenic N-terminal domain of Sup35p and Sup35p is not aggregated in [ISP+] cells, thus ruling out the possibility that [ISP+] is a specific form of [PSI+]. We hypothesize that [ISP+] is a novel prion involved in the control of translation accuracy in yeast.

The molecular nature of the sup45 respiratory deficient omnipotent suppressor, and of three reversions to respiratory competence which removed the suppressor effect of the initial mutation, was examined. All reversions were caused by secondary sup45 mutations which indicates a direct connection between sup45 "respiratory" and "translational" functions. Computer analysis showed the local changes of Sup45 protein characteristics in the suppressor strain and revertants in comparison to the wild-type protein. The distribution of mutant sites in relation to evolutionary conserved, and tentatively functional, regions in the Sup45 protein is discussed.