title: CHK2-BRCA1 tumor-suppressor axis restrains oncogenic Aurora-A kinase to ensure proper mitotic microtubule assembly.
abstract: BRCA1 (breast cancer type 1 susceptibility protein) is a multifunctional tumor suppressor involved in DNA damage response, DNA repair, chromatin regulation, and mitotic chromosome segregation. Although the nuclear functions of BRCA1 have been investigated in detail, its role during mitosis is little understood. It is clear, however, that loss of BRCA1 in human cancer cells leads to chromosomal instability (CIN), which is defined as a perpetual gain or loss of whole chromosomes during mitosis. Moreover, our recent work has revealed that the mitotic function of BRCA1 depends on its phosphorylation by the tumor-suppressor kinase Chk2 (checkpoint kinase 2) and that this regulation is required to ensure normal microtubule plus end assembly rates within mitotic spindles. Intriguingly, loss of the positive regulation of BRCA1 leads to increased oncogenic Aurora-A activity, which acts as a mediator for abnormal mitotic microtubule assembly resulting in chromosome missegregation and CIN. However, how the CHK2-BRCA1 tumor suppressor axis restrains oncogenic Aurora-A during mitosis to ensure karyotype stability remained an open question. Here we uncover a dual molecular mechanism by which the CHK2-BRCA1 axis restrains oncogenic Aurora-A activity during mitosis and identify BRCA1 itself as a target for Aurora-A relevant for CIN. In fact, Chk2-mediated phosphorylation of BRCA1 is required to recruit the PP6C-SAPS3 phosphatase, which acts as a T-loop phosphatase inhibiting Aurora-A bound to BRCA1. Consequently, loss of CHK2 or PP6C-SAPS3 promotes Aurora-A activity associated with BRCA1 in mitosis. Aurora-A, in turn, then phosphorylates BRCA1 itself, thereby inhibiting the mitotic function of BRCA1 and promoting mitotic microtubule assembly, chromosome missegregation, and CIN.
authors.affiliation: Section for Cellular Oncology, Institute of Molecular Oncology, University Medical Center Göttingen, D-37077 Göttingen, Germany; Göttingen Center for Molecular Biosciences (GZMB), Georg-August University Göttingen, D-37077 Göttingen, Germany;
authors.forename: Norman
authors.initials: N
authors.lastname: Ertych
authors.affiliation: Section for Cellular Oncology, Institute of Molecular Oncology, University Medical Center Göttingen, D-37077 Göttingen, Germany; Göttingen Center for Molecular Biosciences (GZMB), Georg-August University Göttingen, D-37077 Göttingen, Germany;
authors.forename: Ailine
authors.initials: A
authors.lastname: Stolz
authors.affiliation: Göttingen Center for Molecular Biosciences (GZMB), Georg-August University Göttingen, D-37077 Göttingen, Germany; Department for Molecular Microbiology and Genetics, Institute of Microbiology and Genetics, Georg-August University Göttingen, D-37077 Göttingen, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Valerius
authors.affiliation: Göttingen Center for Molecular Biosciences (GZMB), Georg-August University Göttingen, D-37077 Göttingen, Germany; Department for Molecular Microbiology and Genetics, Institute of Microbiology and Genetics, Georg-August University Göttingen, D-37077 Göttingen, Germany.
authors.forename: Gerhard H
authors.initials: GH
authors.lastname: Braus
authors.affiliation: Section for Cellular Oncology, Institute of Molecular Oncology, University Medical Center Göttingen, D-37077 Göttingen, Germany; Göttingen Center for Molecular Biosciences (GZMB), Georg-August University Göttingen, D-37077 Göttingen, Germany; holger.bastians@uni-goettingen.de.
authors.forename: Holger
authors.initials: H
authors.lastname: Bastians
mesh_terms: D064096:Aurora Kinase A / Q000378:metabolism*; D019313:BRCA1 Protein / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D064447:Checkpoint Kinase 2 / Q000235:genetics / Q000502:physiology*; D016147:Genes, Tumor Suppressor; D006801:Humans; D008870:Microtubules / Q000378:metabolism*; D008938:Mitosis
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D064447:Checkpoint Kinase 2; C576917:AURKA protein, human; D064096:Aurora Kinase A; C578634:CHEK2 protein, human
keywords: aneuploidy; chromosome segregation; mitosis; protein phosphatase; tumor suppressor
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