RT Journal Article
SR Electronic
T1 Proper chromosome alignment depends on BRCA2 phosphorylation by PLK1
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 265934
DO 10.1101/265934
A1 Åsa Ehlén
A1 Charlotte Martin
A1 Manon Julien
A1 Simona Miron
A1 François-Xavier Theillet
A1 Virginie Boucherit
A1 Patricia Duchambon
A1 Ahmed El Marjou
A1 Sophie Zinn-Justin
A1 Aura Carreira
YR 2018
UL http://biorxiv.org/content/early/2018/03/08/265934.abstract
AB The BRCA2 tumor suppressor protein is involved in the maintenance of genome integrity through its role in homologous recombination (HR) in S/G2 phases of the cell cycle. In mitosis, BRCA2 participates in the spindle assembly checkpoint (SAC) via its interaction with the SAC component BUBR1 and is involved in cytokinesis. BRCA2 is phosphorylated by the cell cycle regulator Polo-like kinase 1 (PLK1), although the functional relevance of this phosphorylation remains unclear. Here we show that proper chromosome alignment depends on BRCA2 phosphorylation by PLK1. We combined nuclear magnetic resonance spectroscopy, isothermal titration calorimetry and cell biology to characterize the phenotype of BRCA2 variants that alter PLK1 phosphorylation. We identified T207 of BRCA2 as a bona fide docking site for PLK1 required for the phosphorylation of BUBR1 and the full alignment of the chromosomes at the metaphase plate. Precluding T207 binding to PLK1 as observed in BRCA2 missense variants identified in breast cancer results in reduced phosphorylation of BUBR1 at PLK1-dependent sites leading to severe chromosome misalignment and segregation errors. We thus reveal a direct role of BRCA2 in the alignment of chromosomes separate from DNA repair. These findings may explain in part the aneuploidy observed in BRCA2-deficient tumors.