HSP90 buffers deleterious genetic variations in .

Protein-folding chaperone HSP90 buffers genetic variation in diverse organisms, but the clinical significance of HSP90 buffering in disease remains unclear. Here, we show that HSP90 buffers mutations in the BRCT domain of BRCA1. HSP90-buffered mutations encode protein variants that retain interactions with partner proteins and rely on HSP90 for protein stability and function in cell survival.

Selection for robust metabolism in domesticated yeasts is driven by adaptation to Hsp90 stress.

Protein folding both promotes and constrains adaptive evolution. We uncover this surprising duality in the role of the protein-folding chaperone heat shock protein 90 (Hsp90) in maintaining the integrity of yeast metabolism amid proteotoxic stressors within industrial domestication niches. Ethanol disrupts critical Hsp90-dependent metabolic pathways and exerts strong selective pressure for redundant duplications of key genes within these pathways, yielding the classical genomic signatures of beer and bread domestication.

Protein-folding chaperones predict structure-function relationships and cancer risk in BRCA1 mutation carriers.

Predicting the risk of cancer mutations is critical for early detection and prevention, but differences in allelic severity of human carriers confound risk predictions. Here, we elucidate protein folding as a cellular mechanism driving differences in mutation severity of tumor suppressor BRCA1. Using a high-throughput protein-protein interaction assay, we show that protein-folding chaperone binding patterns predict the pathogenicity of variants in the BRCA1 C-terminal (BRCT) domain.

Ethanol Drives Evolution of Hsp90-Dependent Robustness by Redundancy in Yeast Domestication.

Protein folding promotes and constrains adaptive evolution. We uncover this surprising duality in the role the protein-folding chaperone Hsp90 plays in mediating the interplay between proteome and the genome which acts to maintain the integrity of yeast metabolism in the face of proteotoxic stressors in anthropic niches. Of great industrial relevance, ethanol concentrations generated by fermentation in the making of beer and bread disrupt critical Hsp90-dependent nodes of metabolism and exert strong selective pressure for increased copy number of key genes encoding components of these nodes, yielding the classical genetic signatures of beer and bread domestication.

Protein-Folding Chaperones Predict Structure-Function Relationships and Cancer Risk in Mutation Carriers.

Unlabelled: Identifying pathogenic mutations and predicting their impact on protein structure, function and phenotype remain major challenges in genome sciences. Protein-folding chaperones participate in structure-function relationships by facilitating the folding of protein variants encoded by mutant genes. Here, we utilize a high-throughput protein-protein interaction assay to test HSP70 and HSP90 chaperone interactions as predictors of pathogenicity for variants in the tumor suppressor BRCA1.

Noncanonical role of the 9-1-1 clamp in the error-free DNA damage tolerance pathway.

Damaged DNA is an obstacle during DNA replication and a cause of genome instability and cancer. To bypass this problem, eukaryotes activate DNA damage tolerance (DDT) pathways that involve ubiquitylation of the DNA polymerase clamp proliferating cell nuclear antigen (PCNA). Monoubiquitylation of PCNA mediates an error-prone pathway by recruiting translesion polymerases, whereas polyubiquitylation activates an error-free pathway that utilizes undamaged sister chromatids as templates.