The BRCA2 protein, produced by the expression of the tumor suppressor gene BRCA2, plays an important role in DNA repair by homologous recombination, which takes place at early phases of the cell cycle. A team from Institut Curie, in collaboration with a group of CEA, revealed an additional role of BRCA2 in the alignment of chromosomes during mitosis (cell division), with significant consequences on chromosome stability. Published in Nature Communications, these results could explain certain chromosomal aberrations observed in BRCA2 mutated tumors.
The “Genome Instability and Cancer Predisposition” team led by Aura Carreira in the “Genome integrity, RNA and Cancer” unit (CNRS/Paris-Saclay university/Institut Curie) is working on the role of BRCA2 in maintaining genome integrity. We know that BRCA2 operates in DNA repair by homologous recombination, the DNA duplication phase of the cell cycle. In addition, we know that a mutation in the BRCA2 gene predisposes to breast and ovarian cancer.
In collaboration with Sophie Zinn-Justin’s group at the CEA, Aura Carreira’s team found an additional and unexpected role of BRCA2 in mitosis, which seems uncoupled to its function in DNA repair. Using a combination of biophysical, biochemistry, cell biology and genetics tools, these researchers showed that the alignment of chromosomes at the metaphase plate depends on the phosphorylation of BRCA2 by the protein kinase PLK1. Importantly, they found that certain BRCA2 variants identified in breast cancer patients this function during mitosis is altered.
“These results reveal a novel function of BRCA2 that could contribute to the numerical chromosomal aberrations that are often observed in BRCA2 mutated tumors,” explains Aura Carreira.
The phosphorylation of BRCA2 by PLK1 at the kinetochore (illustrated as “P”) during mitosis facilitates the alignment of chromosomes at the metaphase plate. Certain BRCA2 variants identified in breast cancer patients impair this phosphorylation, which leads to defects in the alignment and segregation of chromosomes resulting in numerical chromosomal aberrations. (aneuploidy).
Proper Chromosome Alignment Depends on BRCA2 Phosphorylation by PLK1. Åsa Ehlén, Charlotte Martin, Simona Miron, Manon Julien, François-Xavier Theillet, Virginie Ropars, Gaetana Sessa, Romane Beaurepere, Virginie Boucherit, Patricia Duchambon, Ahmed El Marjou, Sophie Zinn-Justin, Aura Carreira. Nature Communications. April 14l 2020. doi: 10.1038/s41467-020-15689-9.