Every human cell carries thousands of genetic mutations, most of which cause no noticeable harm. For decades, this was a puzzle: how can the genome tolerate so much variation without collapsing into disease? The answer, it turns out, lies in a class of molecular chaperones, proteins whose job is to keep other proteins properly folded, that act as a hidden buffer between genetic errors and their consequences.
A Nature News Feature published June 17 by science writer Philip Ball details the emerging understanding of this “mutational buffering” system, centered on the heat-shock protein HSP90, and the surprising ways it is reshaping our understanding of cancer, evolution, and treatment resistance.
The concept traces back to seminal 1998 work by Suzanne Rutherford and Susan Lindquist, who showed that HSP90 acts as a “capacitor for morphological evolution”, it accumulates hidden genetic variation in populations, masking mutations that would otherwise cause observable defects. When the system is stressed, the buffer fails, and hidden traits are suddenly revealed.
HSP90 is one of the most abundant proteins in human cells, roughly 1% of total cellular protein. As a molecular chaperone, its job is to help misfolded proteins refold correctly. When a mutation changes a protein’s amino acid sequence, that protein may be slightly unstable. HSP90 can often fix it, keeping the mutant protein functional and preventing the mutation from causing a detectable effect.
The cancer connection
The clinical implications are most dramatic in cancer. Georgios Karras, associate professor of genetics at the University of Texas MD Anderson Cancer Center, has studied how HSP90 buffers mutations in the tumor suppressor BRCA1, the gene best known for its role in hereditary breast and ovarian cancer.
Mutations in BRCA1 usually increase cancer risk. But HSP90 can stabilize certain mutant BRCA1 proteins, keeping them partially functional and delaying early-life cancer onset in carriers. This sounds beneficial, until you consider treatment. PARP inhibitors, a major class of breast cancer drugs, work by exploiting the vulnerability created by BRCA1 loss-of-function. If HSP90 is keeping mutant BRCA1 on life support, the cells become resistant to PARP inhibition.
The solution is elegant: low-dose HSP90 inhibition can restore PARP inhibitor sensitivity in cancer cells carrying HSP90-buffered BRCA1 mutations. Potent, highly selective HSP90 inhibitors already exist and are showing promise in clinical trials. Researchers have identified predictive features to determine which patients would benefit most from this combination approach.
A key 2025 study led by B. Gracia and published in Molecular Cell (DOI: 10.1016/j.molcel.2025.10.026) showed that HSP90 buffers approximately 18% of known missense mutations in the BRCT domain of BRCA1. This means that nearly one in five disease-associated BRCA1 mutations may have their effects masked by chaperone activity, a factor that must be accounted for in genetic risk assessment.
Beyond the heat shock
The buffering phenomenon extends well beyond HSP90. A 2024 yeast study screened thousands of genes for buffering capacity and identified a second functional category: chromatin-organising proteins. Kevin Verstrepen, a geneticist at VIB-KU Leuven in Belgium, has shown that these proteins contribute to the same hidden-variation phenomenon through a different mechanism, by regulating how genes are packaged and accessed rather than by folding proteins.
Christine Queitsch, a genomicist at the University of Washington, has studied how HSP90 buffering interacts with environmental stress. Fever, for example, temperatures of 39-40°C, can exhaust HSP90’s capacity, unmasking hidden mutations. This may explain why certain genetic conditions first appear during illness, and it has direct implications for Fanconi anaemia, a DNA repair disorder in which HSP90-buffered FANCA mutations can become clinically significant under heat stress.
The therapeutic frontier
The practical applications are taking shape in the clinic. Beyond BRCA1, HSP90 client proteins include hormone receptors, transcription factors, and cell-signalling molecules, all common targets in cancer therapy. Low-dose HSP90 inhibition may offer a way to sensitize tumors across multiple cancer types without the toxicity that plagued early, high-dose HSP90 inhibitor trials.
“As the past few years have made clear, advances have shifted our view on HSP90 buffering from a theoretical idea to one with immediate and important practical applications, especially in the clinic,” Karras told Nature.
Source: Nature News Feature, “These ‘master’ proteins protect us from deadly mutations, and could inspire new drugs” by Philip Ball (June 17, 2026). Nature vol. 654, pp. 586-588. DOI: 10.1038/d41586-026-01883-0.