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.
Cell Rep. 2024 Feb 27;43(2):113803. doi: 10.1016/j.celrep.2024.113803. Epub 2024 Feb 17.
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.
预测癌症突变的风险对于早期检测和预防至关重要，但人类携带者等位基因严重程度的差异会干扰风险预测。在这里，我们阐明了蛋白质折叠作为一种细胞机制，驱动肿瘤抑制因子 BRCA1 突变严重程度的差异。我们使用高通量蛋白质-蛋白质相互作用测定法，表明蛋白质折叠伴侣的结合模式可以预测 BRCA1 C 末端（BRCT）结构域中变体的致病性。HSP70 选择性地结合 94%的致病性 BRCA1-BRCT 变体，其中大多数与 HSP70 的结合程度超过 HSP90。值得注意的是，HSP70 结合的幅度与折叠和功能的丧失呈线性相关。我们鉴定出一种常见的人类功能减弱型 BRCA1 变体，这些变体与伴侣蛋白中度结合，并保留部分折叠和功能。此外，伴侣蛋白的结合表明在临床上具有更高的突变外显率和更早的癌症发病。我们的发现证明了伴侣蛋白作为变体折叠、表型严重程度和癌症风险的定量细胞生物传感器的实用性。
