Patients affected by familial forms of breast or ovarian cancer generally undergo genetic testing, which involves the sequencing of the breast cancer 1 (BRCA1) gene, because carriers of pathogenic mutations in this gene require specific clinical follow-ups and treatments. However, a major obstacle with genetic testing is proving that a DNA variation found in a susceptibility gene is pathogenic, meaning that it is associated with disease development. To solve this, in vitro assays have been developed to evaluate the impact of the BRCA1 mutations on the protein structure or function. On page 4366 in this issue, Gaël Millot and colleagues show that, when expressed in yeast Saccharomyces cerevisiae cells, the wild-type human BRCA1 protein is localised in the nucleus, as it is in human cells, except that the protein aggregates in the yeast nucleus. Importantly, mutations leading to a misfolding of BRCA1 result in a cytoplasmic delocalisation of the protein in both yeast and human cells, revealing a connection between protein misfolding and nuclear transport impairment. Finally, this work demonstrates the suitability of the yeast model for misfolding-mutation studies of factors implicated in human diseases.
