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Scientific result | Molecular mechanisms | Cancer
In a study conducted by a team from the Institut Curie, I2BC researchers have used their NMR know-how to study the phosphorylation of BRCA2 and have thus contributed to revealing a mechanism potentially at the origin of chromosomal aberrations observed in breast BRCA2-mutated tumors.
BRCA2 is one of the predisposition genes for breast and ovarian cancers. To date, this predisposition has been attributed primarily to the function in DNA repair of the protein encoded by the BRCA2 gene. What if another BRCA2 function is responsible or co-responsible for this pathophysiological mechanism? Recent studies have highlighted a role of the protein in the course of mitosis. BRCA2 is phosphorylated by the PLK1 kinase during mitosis without knowing precisely where in its sequence and why.
As a starting point for a new study on BRCA2, teams from the Institut Curie and the Institut Joliot (Structural Biology and Radiobiology Laboratory - LBSR / I2BC) identified that three mutations found in patients were capable of decreasing in vitro the phosphorylation of BRCA2 by PLK1: S193A, T207A and S206C. Also in vitro, using nuclear magnetic resonance experiments, Sophie Zinn-Justin's team (LBSR) showed that threonine 207 is phosphorylated by PLK1 and that the T207A mutation alters the global phosphorylation kinetics of BRCA2. By resolving the structure of PLK1 into a complex with a BRCA2 peptide containing phosphorylated T207, the LBSR team showed that T207 constitutes a bona fide docking site for PLK1. Studies carried out on culture cells by the Institut Curie team show that the docking of PLK1 at T207-BRCA2 favors a tetracomplex of the two proteins with BURB1 and PP2A. BURB1 facilitates kinetochore-microtubule attachments via its interaction with PP2A, a linkage that is essential for the correct placement of chromosomes during cell division. Phosphorylation of BRCA2 by PLK1 would contribute directly to the alignment of chromosomes at the metaphase plate. This observation would explain at least in part the aneuploidy observed in BRCA2-mutated tumors. Another important observation is that mutations at the S193 and T207 phosphorylation sites are only weakly sensitive to DNA damage, indicating that the function of BRCA2 during mitosis is independent of its function in homologous recombination repair.
In summary, these results reveal a novel mechanism that may contribute to the chromosomal aberrations observed in BRCA2-mutated tumors. They have been published in Nature Communications. To further investigate the analysis of phosphorylations of the unfolded protein domains, the LBSR team has developed a new method described in Angewangte Chemie, which makes it possible to monitor these phosphorylations over a very wide range of pH and temperature.
C. Martin, S. Miron, M. Julien, F-X. Theillet, V. Ropars,
G. Sessa, R. Beaurepere, V. Boucherit, P. Duchambon, A. El Marjou, S. Zinn-Justin & A. Carreira. Proper chromosome alignment depends on BRCA2 phosphorylation by PLK1. | Nature
A. Alik, C. Bouguechtouli, M. Julien, W. Bermel, R. Ghouil, S. Zinn‐Justin, F‐X.
13C‐NMR Spectroscopy for Monitoring Multisite Phosphorylation at Physiological
Temperature and pH. | Angewandte
CEA is a French government-funded technological research organisation in four main areas: low-carbon energies, defense and security, information technologies and health technologies. A prominent player in the European Research Area, it is involved in setting up collaborative projects with many partners around the world.