Protein-Folding Chaperones Predict Structure-Function Relationships and Cancer Risk in BRCA1 Mutation Carriers

Area of Science:

• Genomics and molecular biology
• Protein science
• Cancer genetics

Background:

• Identifying pathogenic mutations and predicting their functional impact are critical challenges in genome sciences.
• Protein-folding chaperones are crucial for maintaining protein structure-function relationships, especially for mutant variants.
• The tumor suppressor gene BRCA1 is frequently mutated in hereditary breast and ovarian cancers.

Approach:

• A high-throughput protein-protein interaction assay was employed to assess HSP70 and HSP90 chaperone binding to BRCA1 variants.
• Chaperone interactions were quantitatively analyzed to predict variant pathogenicity and functional impact.
• The study correlated chaperone binding levels with structural defects, phenotypic severity, and cancer risk in BRCA1 carriers.

Key Points:

• Chaperones bind 77% of pathogenic BRCA1-BRCT variants, with a preference for HSP70 over HSP90.
• The extent of chaperone binding is proportional to the structural and phenotypic severity caused by BRCA1 mutations.
• Quantitative chaperone interaction data identified variants missed by existing pathogenicity prediction algorithms, including separation-of-function and hypomorphic alleles.

Conclusions:

• Chaperones serve as effective cellular biosensors for detecting pathogenic folding variants in BRCA1.
• The degree of chaperone binding accurately reflects the severity of structural and phenotypic defects associated with BRCA1 mutations.
• Chaperone interactions provide insights into the penetrance and expressivity of different BRCA1 alleles, aiding in cancer risk assessment.