Proper chromosome alignment depends on BRCA2 phosphorylation by PLK1

Abstract

<jats:title>Summary</jats:title><jats:p>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 identified two highly conserved phosphorylation sites at S193 and T207 of BRCA2. Phosphorylated-T207 is a <jats:italic>bona fide</jats:italic> docking site for PLK1 as illustrated by the crystal structure of the BRCA2 peptide bound to PLK1 Polo-box domain. We found that BRCA2 bound to PLK1 forms a complex with the phosphatase PP2A and phosphorylated-BUBR1. Reducing BRCA2 binding to PLK1, as observed in <jats:italic>BRCA2</jats:italic> breast cancer variants S206C and T207A, alters the tetrameric complex resulting in misaligned chromosomes, faulty chromosome segregation and aneuploidy. We thus reveal a direct 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 <jats:italic>BRCA2</jats:italic>-mutated tumors.</jats:p>

Replication gap suppression depends on the double-strand DNA binding activity of BRCA2

“…Finally, replication-associated gaps may result in regions of unreplicated DNA that could lead to chromatin bridges in anaphase. Therefore, we analyzed the presence of chromosome segregation errors by looking at anaphase bridges as previously shown in BRCA2-deficient cells 54 , 55 . We found a slight increase in the number of cells with anaphase bridges in the BRCA2-C315S cell line compared to BRCA2 WT cells measured in unperturbed conditions which were accentuated in BRCA2-deficient cells (Fig.…”

Sensitivity‐Enhanced 13C‐NMR Spectroscopy for Monitoring Multisite Phosphorylation at Physiological Temperature and pH

“…) and the pluripotency transcription factor Oct4 (aa1–145; Supporting Information, Figure S7). Our characterization of BRCA2 phosphorylation by Plk1 (pH 7.8, T =303 K), an important mitotic event, permitted the quantification of two novel phosphosites, namely Thr219 and Thr226, which were modified with rates comparable to the previously reported Ser193 and Thr207 (Figure a,c) . We also wanted to examine Oct4 phosphorylation by MAP kinase, which regulates Oct4 transcriptional activity .…”

The Eyes Absent family members EYA4 and EYA1 promote PLK1 activation and successful mitosis through tyrosine dephosphorylation

“…Total spindle defects were strongly induced by treatment with benzarone (p < 0.001, Figure 3G-H). Monopolar spindles and spindles with misaligned chromosomes, two defects known to be caused by PLK1 deficiency, were frequently observed following combined depletion of EYA4 and EYA1, or benzarone treatment (p < 0.001, Figure S3B) [44][45][46][47] .…”