Abstract
Protein-folding chaperone heat shock protein 90 (HSP90) buffers genetic variation in diverse organisms, but the clinical significance of HSP90 buffering in human disease remains unclear. Here, we show that HSP90 buffers mutations in the BRCT domain of BRCA1. HSP90-buffered BRCA1 mutations result in protein variants that retain interactions with partner proteins and strongly rely on HSP90 for protein stability and function in cell survival. Moreover, HSP90-buffered BRCA1 variants confer poly (ADP-ribose) polymerase (PARP) inhibitor resistance in cancer cells. Low-level HSP90 inhibition overcomes this resistance, revealing a cryptic and mutant-specific HSP90-contingent synthetic lethality. Furthermore, 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 18% 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 therapy resistance and cancer predisposition.