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FASEB J. 2014 Dec;28(12):5250-61. doi: 10.1096/fj.14-250266. Epub 2014 Sep 9.

Loss of BRCA1 impairs centromeric cohesion and triggers chromosomal instability.

Author information

1
Institute of Pharmacology and Structural Biology, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 5089, Toulouse, France; University of Toulouse, Université Paul Sabatier, Toulouse, France; and.
2
Institute of Pharmacology and Structural Biology, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 5089, Toulouse, France; University of Toulouse, Université Paul Sabatier, Toulouse, France; and Equipe Labellisée Ligue Nationale contre le Cancer, Toulouse, France.
3
Institute of Pharmacology and Structural Biology, Centre National de la Recherche Scientifique (CNRS), Unité Mixte de Recherche (UMR) 5089, Toulouse, France; University of Toulouse, Université Paul Sabatier, Toulouse, France; and larminat@ipbs.fr.

Abstract

In contrast to its well-known role in the DNA damage response during interphase, the function of BRCA1 in the maintenance of chromosomal stability during mitosis remains to be defined. In this study, we uncover a novel role of BRCA1 in preserving centromere integrity in mitotic human cells. Using immunofluorescence and chromatin immunoprecipitation approaches, we report BRCA1 association with centromeric chromatin during mitosis. BRCA1 depletion impairs centromeric cohesion, leading to an increase in interkinetochore distance and in unpaired sister-chromatids frequency during prometaphase. Moreover, BRCA1 loss partially decreased accumulation of the Aurora B kinase at the centromere. We found that proper recruitment of the DNMT3b DNA methyltransferase to satellite sequences is BRCA1-dependent during mitosis, suggesting that DNA hypomethylation contributes to Aurora B mislocalization. BRCA1-deficient cells exhibited decreased ability to correct improper Aurora B-dependent chromosome-spindle attachments and to align chromosomes at metaphase. Finally, we show that BRCA1 disruption promotes merotelic kinetochore attachments that represent a major mechanism of aneuploidy in human cells. In summary, we report here a novel function of BRCA1 in maintaining chromosomal stability through its contribution to the mitotic centromere integrity necessary for faithful segregation of sister-chromatids during cell division.

KEYWORDS:

aneuploidy; chromosome-spindle attachment; mitosis

PMID:
25205741
DOI:
10.1096/fj.14-250266
[Indexed for MEDLINE]

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