Journal Article Ppublish 7 citations
PubMed: 38368609 DOI: 10.1016/j.celrep.2024.113803
Protein-folding chaperones predict structure-function relationships and cancer risk in BRCA1 mutation carriers.
Cell Rep 43(2):113803
Authors: Brant Gracia, Patricia Montes, Angelica Maria Gutierrez, Banu Arun, Georgios Ioannis Karras
Affiliations
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
- Department of Breast Medical Oncology and Clinical Cancer Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Genetics and Epigenetics Graduate Program, The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, USA.
Abstract
Predicting the risk of cancer mutations is critical for early detection and prevention, but differences in allelic severity of human carriers confound risk predictions. Here, we elucidate protein folding as a cellular mechanism driving differences in mutation severity of tumor suppressor BRCA1. Using a high-throughput protein-protein interaction assay, we show that protein-folding chaperone binding patterns predict the pathogenicity of variants in the BRCA1 C-terminal (BRCT) domain. HSP70 selectively binds 94% of pathogenic BRCA1-BRCT variants, most of which engage HSP70 more than HSP90. Remarkably, the magnitude of HSP70 binding linearly correlates with loss of folding and function. We identify a prevalent class of human hypomorphic BRCA1 variants that bind moderately to chaperones and retain partial folding and function. Furthermore, chaperone binding signifies greater mutation penetrance and earlier cancer onset in the clinic. Our findings demonstrate the utility of chaperones as quantitative cellular biosensors of variant folding, phenotypic severity, and cancer risk.
MeSH
Genetic Variation, Biological Science Disciplines, Neoplasms, Risk, Penetrance, Genes, Brca1, Mutation