The fidelity of DNA replication, particularly on GC-rich templates, is reduced by defects of the Fe-S cluster in DNA polymerase δ.

Iron-sulfur clusters (4Fe-4S) exist in many enzymes concerned with DNA replication and repair. The contribution of these clusters to enzymatic activity is not fully understood. We identified the MET18 (MMS19) gene of Saccharomyces cerevisiae as a strong mutator on GC-rich genes.

Role of the Cell Asymmetry Apparatus and Ribosome-Associated Chaperones in the Destabilization of a Prion by Heat Shock.

Self-perpetuating transmissible protein aggregates, termed prions, are implicated in mammalian diseases and control phenotypically detectable traits in Yeast stress-inducible chaperone proteins, including Hsp104 and Hsp70-Ssa that counteract cytotoxic protein aggregation, also control prion propagation. Stress-damaged proteins that are not disaggregated by chaperones are cleared from daughter cells via mother-specific asymmetric segregation in cell divisions following heat shock. Short-term mild heat stress destabilizes [ ], a prion isoform of the yeast translation termination factor Sup35 This destabilization is linked to the induction of the Hsp104 chaperone.

GC content elevates mutation and recombination rates in the yeast .

The chromosomes of many eukaryotes have regions of high GC content interspersed with regions of low GC content. In the yeast , high-GC regions are often associated with high levels of meiotic recombination. In this study, we constructed genes that differ substantially in their base composition [ (31% GC), (43% GC), and (63% GC)] but encode proteins with the same amino acid sequence.

Yeast Short-Lived Actin-Associated Protein Forms a Metastable Prion in Response to Thermal Stress.

Self-perpetuating ordered protein aggregates (amyloids and prions) are associated with a variety of neurodegenerative disorders. Although environmental agents have been linked to certain amyloid diseases, the molecular basis of their action remains unclear. We have employed endogenous yeast prions as a model system to study environmental control of amyloid formation.

Dual role of ribosome-associated chaperones in prion formation and propagation.

Chaperones of the diverse ubiquitous Hsp70 family are involved in the regulation of ordered self-perpetuating protein aggregates (amyloids and prions), implicated in both devastating diseases and protein-based inheritance. Yeast ribosome-associated chaperone complex (RAC), composed of the Hsp40 protein Zuo1 and non-canonical Hsp70 protein Ssz1, mediates association of the Hsp70 chaperone Ssb with translating ribosomes. Ssb participates in co-translational protein folding, regulation of premature translation termination, and ribosome biogenesis.

Feedback control of prion formation and propagation by the ribosome-associated chaperone complex.

Cross-beta fibrous protein aggregates (amyloids and amyloid-based prions) are found in mammals (including humans) and fungi (including yeast), and are associated with both diseases and heritable traits. The Hsp104/70/40 chaperone machinery controls propagation of yeast prions. The Hsp70 chaperones Ssa and Ssb show opposite effects on [PSI(+)], a prion form of the translation termination factor Sup35 (eRF3).

Regulation of chaperone effects on a yeast prion by cochaperone Sgt2.

Yeast prions, based on self-seeded highly ordered fibrous aggregates (amyloids), serve as a model for human amyloid diseases. Propagation of yeast prions depends on the balance between chaperones of the Hsp100 and Hsp70 families. The yeast prion [PSI(+)] can be eliminated by an excess of the chaperone Hsp104.