Raw data repository of "HSP90 buffers deleterious genetic variations in BRCA1"

All raw data included in figures and uncropped Western blots of the manuscript "HSP90 buffers deleterious genetic variations in BRCA1".
Cite this article as: Brant Gracia (1,4), Xing-Han Zhang (1,3,4), Patricia Montes (1), Tin Chanh Pham (1), Min Huang (2), Junjie Chen (2) and Georgios Ioannis Karras (1,3,5,6,*). HSP90 buffers deleterious genetic variations in BRCA1, Molecular Cell, doi:10.1016/j.molcel.2025.10.026

Affiliations:
(1) Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
(2) Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA 3Genetics and Epigenetics Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX 77030, USA
(4) These authors contributed equally
(5) Senior author
(6) Lead contact
*Correspondence: [e-mail]
https://doi.org/10.1016/j.molcel.2025.10.026

We report that HSP90 buffers mutations in the essential tumor suppressor, BRCA1, the poster child gene of precision medicine. BRCA1-inactivating mutations predispose human carriers to various cancers by compromising genome maintenance pathways critical for cellular fitness. Such mutations typically disrupt the recruitment of critical DNA repair protein partners to key domains of BRCA1, especially the C-terminal BRCT domain (BRCA1-BRCT). HSP90-buffered BRCA1-BRCT variants retain physiological interactions with partners and support cell fitness but show increased dependence on HSP90 for their stability and function. Low-level, nontoxic concentrations of HSP90 inhibitors synergize with PARP inhibition to kill cancer cells expressing HSP90-buffered BRCA1 mutations but not wild-type cells. HSP90-buffered variants account for 18% of the human BRCA1-BRCT missense variants tested and confer delayed breast cancer onset in patients. Predictive features of HSP90 buffering in BRCA1-BRCT enable stratification of HSP90-buffered mutation carriers, providing a basis for personalized diagnosis, prognosis, and combination therapies with HSP90 inhibitors.