Institut Curie, PSL Research University, CNRS, UMR3348, F-91405, Orsay, France.
Paris Sud University, Paris-Saclay University CNRS, UMR3348, F-91405, Orsay, France.
Nat Commun. 2020 Apr 14;11(1):1819. doi: 10.1038/s41467-020-15689-9.
The BRCA2 tumor suppressor protein is involved in the maintenance of genome integrity through its role in homologous recombination. In mitosis, BRCA2 is phosphorylated by Polo-like kinase 1 (PLK1). Here we describe how this phosphorylation contributes to the control of mitosis. We identify a conserved phosphorylation site at T207 of BRCA2 that constitutes a bona fide docking site for PLK1 and is phosphorylated in mitotic cells. We show that BRCA2 bound to PLK1 forms a complex with the phosphatase PP2A and phosphorylated-BUBR1. Reducing BRCA2 binding to PLK1, as observed in BRCA2 breast cancer variants S206C and T207A, alters the tetrameric complex resulting in unstable kinetochore-microtubule interactions, misaligned chromosomes, faulty chromosome segregation and aneuploidy. We thus reveal a role of BRCA2 in the alignment of chromosomes, distinct from its DNA repair function, with important consequences on chromosome stability. These findings may explain in part the aneuploidy observed in BRCA2-mutated tumors.
BRCA2 肿瘤抑制蛋白通过参与同源重组在维持基因组完整性方面发挥作用。在有丝分裂过程中，BRCA2 被 Polo 样激酶 1（PLK1）磷酸化。在这里，我们描述了这种磷酸化如何控制有丝分裂。我们确定了 BRCA2 上 T207 处的一个保守磷酸化位点，该位点构成了 PLK1 的真正对接位点，并在有丝分裂细胞中被磷酸化。我们表明，与 PLK1 结合的 BRCA2 与磷酸酶 PP2A 和磷酸化的 BUBR1 形成复合物。如 BRCA2 乳腺癌变体 S206C 和 T207A 中观察到的那样，BRCA2 与 PLK1 的结合减少会改变四聚体复合物，导致动粒微管相互作用不稳定、染色体不对齐、染色体分离错误和非整倍体。因此，我们揭示了 BRCA2 在染色体排列中的作用，与它的 DNA 修复功能不同，对染色体稳定性有重要影响。这些发现部分解释了在 BRCA2 突变肿瘤中观察到的非整倍体。
