Gracia, B. | bioRxiv Science

bioRxiv2024

HSP90 buffers deleterious genetic variations in BRCA1

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 BRCA1 mutations encode protein variants that retain interactions with partner proteins and rely on HSP90 for protein stability and function in cell survival. Moreover, HSP90-buffered BRCA1 variants confer PARP inhibitor resistance in cancer cell lines. Low-level HSP90 inhibition alleviates this resistance, revealing a cryptic and mutant-specific HSP90-contingent synthetic lethality. Hence, by stabilizing metastable variants across the entirety of the BRCT domain, HSP90 reduces the clinical severity of BRCA1 mutations allowing them to accumulate in populations. We estimate that HSP90 buffers 11% to 28% of known human BRCA1- BRCT missense mutations. Our work extends the clinical significance of HSP90 buffering to a prevalent class of variations in BRCA1, pioneering its importance in cancer predisposition and therapy resistance.

genetics↗

bioRxiv2023

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

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. Chaperones bind 77% of pathogenic BRCA1-BRCT variants, most of which engaged HSP70 more than HSP90. Remarkably, the magnitude of chaperone binding to variants is proportional to the degree of structural and phenotypic defect induced by BRCA1 mutation. Quantitative chaperone interactions identified BRCA1-BRCT separation-of-function variants and hypomorphic alleles missed by pathogenicity prediction algorithms. Furthermore, increased chaperone binding signified greater cancer risk in human BRCA1 carriers. Altogether, our study showcases the utility of chaperones as quantitative cellular biosensors of variant folding and phenotypic severity. HIGHLIGHTSO_LIChaperones detect an abundance of pathogenic folding variants of BRCA1-BRCT. C_LIO_LIDegree of chaperone binding reflects severity of structural and phenotypic defect. C_LIO_LIChaperones identify separation-of-function and hypomorphic variants. C_LIO_LIChaperone interactions indicate penetrance and expressivity of BRCA1 alleles. C_LI

biochemistry↗