title: Yeast cells reveal the misfolding and the cellular mislocalization of the human BRCA1 protein.
abstract: Understanding the effect of an ever-growing number of human variants detected by genome sequencing is a medical challenge. The yeast Saccharomyces cerevisiae model has held attention for its capacity to monitor the functional impact of missense mutations found in human genes, including the BRCA1 breast and ovarian cancer susceptibility gene. When expressed in yeast, the wild-type full-length BRCA1 protein forms a single nuclear aggregate and induces a growth inhibition. Both events are modified by pathogenic mutations of BRCA1. However, the biological processes behind these events in yeast remain to be determined. Here, we show that the BRCA1 nuclear aggregation and the growth inhibition are sensitive to misfolding effects induced by missense mutations. Moreover, misfolding mutations impair the nuclear targeting of BRCA1 in yeast cells and in a human cell line. In conclusion, we establish a connection between misfolding and nuclear transport impairment, and we illustrate that yeast is a suitable model to decipher the effect of misfolding mutations.
authors: Institut Curie, PSL Research University, CNRS, UMR3244, 26 rue d'Ulm, Paris F-75005, France.|Sorbonne Universités, UPMC Univ Paris 06, CNRS, UMR3244, Paris F-75005, France.
authors: Pierre
authors: P
authors: Thouvenot
authors: Institut Curie, PSL Research University, CNRS, UMR3244, 26 rue d'Ulm, Paris F-75005, France.|Sorbonne Universités, UPMC Univ Paris 06, CNRS, UMR3244, Paris F-75005, France.
authors: Lou
authors: L
authors: Fourrière
authors: CNRS UMR 8200, Institut de Cancerologie Gustave-Roussy, Université Paris-Saclay, 114 Rue Edouard Vaillant, Villejuif 94805, France.
authors: Elodie
authors: E
authors: Dardillac
authors: Institut Curie, PSL Research University, CNRS, UMR3244, 26 rue d'Ulm, Paris F-75005, France.|Sorbonne Universités, UPMC Univ Paris 06, CNRS, UMR3244, Paris F-75005, France.
authors: Barbara
authors: B
authors: Ben Yamin
authors: Institut Curie, PSL Research University, CNRS, UMR3244, 26 rue d'Ulm, Paris F-75005, France.|Sorbonne Universités, UPMC Univ Paris 06, CNRS, UMR3244, Paris F-75005, France.
authors: Aurianne
authors: A
authors: Lescure
authors: Institut Curie, PSL Research University, CNRS, UMR3244, 26 rue d'Ulm, Paris F-75005, France.|Sorbonne Universités, UPMC Univ Paris 06, CNRS, UMR3244, Paris F-75005, France.
authors: Vincent
authors: V
authors: Lejour
authors: Sorbonne Universités, UPMC Univ Paris 06, CNRS, UMR3244, Paris F-75005, France.|Institut Curie, PSL Research University, CNRS, UMR144, 26 rue d'Ulm, Paris F-75005, France.
authors: Xavier
authors: X
authors: Heiligenstein
authors: Institut Curie, PSL Research University, CNRS, UMR3244, 26 rue d'Ulm, Paris F-75005, France.|Sorbonne Universités, UPMC Univ Paris 06, CNRS, UMR3244, Paris F-75005, France.
authors: Jean-Baptiste
authors: JB
authors: Boulé
authors: Sorbonne Universités, UPMC Univ Paris 06, CNRS, UMR3244, Paris F-75005, France.|Institut Curie, PSL Research University, CNRS, UMR144, 26 rue d'Ulm, Paris F-75005, France.
authors: Maryse
authors: M
authors: Romao
authors: Sorbonne Universités, UPMC Univ Paris 06, CNRS, UMR3244, Paris F-75005, France.|Institut Curie, PSL Research University, CNRS, UMR144, 26 rue d'Ulm, Paris F-75005, France.
authors: Graça
authors: G
authors: Raposo-Benedetti
authors: CNRS UMR 8200, Institut de Cancerologie Gustave-Roussy, Université Paris-Saclay, 114 Rue Edouard Vaillant, Villejuif 94805, France.
authors: Bernard S
authors: BS
authors: Lopez
authors: Institut Curie, PSL Research University, CNRS, UMR3244, 26 rue d'Ulm, Paris F-75005, France.|Sorbonne Universités, UPMC Univ Paris 06, CNRS, UMR3244, Paris F-75005, France.
authors: Alain
authors: A
authors: Nicolas
authors: Institut Curie, PSL Research University, CNRS, UMR3244, 26 rue d'Ulm, Paris F-75005, France gael.millot@curie.fr.|Sorbonne Universités, UPMC Univ Paris 06, CNRS, UMR3244, Paris F-75005, France.
authors: Gaël A
authors: 0000-0002-0591-3509
authors: GA
authors: Millot
mesh_terms: D019313:BRCA1 Protein / Q000737:chemistry* / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D005453:Fluorescence; D006801:Humans; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D019913:Nuclear Localization Signals; D066329:Protein Aggregates; D000072417:Protein Domains; D017510:Protein Folding; D055550:Protein Stability; D021381:Protein Transport; D012441:Saccharomyces cerevisiae / Q000254:growth & development / Q000378:metabolism*
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D019913:Nuclear Localization Signals; D066329:Protein Aggregates
keywords: BRCA1; Cellular localization; Missense mutation; Protein misfolding; Yeast model