HSP90 Buffers Deleterious Genetic Variations in BRCA1

Authors

Brant Gracia
Xing-Han Zhang
Patricia Montes
Tin Chanh Pham
Min Huang
Junjie Chen
Georgios Ioannis Karras

Language

English

Publication Date

12-4-2025

Journal

Molecular Cell

DOI

10.1016/j.molcel.2025.10.026

PMID

41265458

PMCID

PMC12648472

PubMedCentral® Posted Date

11-27-2025

PubMedCentral® Full Text Version

Author MSS

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.

Keywords

Humans, HSP90 Heat-Shock Proteins, BRCA1 Protein, Poly(ADP-ribose) Polymerase Inhibitors, Drug Resistance, Neoplasm, Protein Stability, Breast Neoplasms, Mutation, Missense, Female, Genetic Variation, Mutation, Cell Line, Tumor, BRCA1, HSP90, Mutational Buffer, Protein Folding, Structural Mutations, Breast Cancer, Synthetic Lethality, PARP Inhibition, HSP90 Inhibition, Polytherapy

Published Open-Access

yes

Recommended Citation

Gracia, Brant; Zhang, Xing-Han; Montes, Patricia; et al., "HSP90 Buffers Deleterious Genetic Variations in BRCA1" (2025). Faculty, Staff and Student Publications. 5954.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5954