HSP90 Buffers Deleterious Genetic Variations in BRCA1

Abstract

Protein-folding chaperone 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 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 cells. 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.

Note:
Funding Information: This research was supported by the NIH under Awards F32CA253780 (B. G.) and K22CA222938 (G. I. K.). This work was supported by CPRIT grant RR180005 (G. I. K.), a Kleberg Innovator Award (G. I. K.) by the Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation, and a Basser External Research Grant by the Basser Center for BRCA (G. I. K.).

Declaration of Interests: We have submitted a patent application describing the combination of PARP inhibitors and HSP90 inhibitors in cancer.

Keywords: BRCA1, HSP90, Mutational Buffer, Protein Folding, Structural Mutations, Breast cancer, Synthetic Lethality, PARP Inhibition, HSP90 inhibition, Polytherapy