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Nat Commun. 2015 Jul 9;6:7676. doi: 10.1038/ncomms8676.

CEP63 deficiency promotes p53-dependent microcephaly and reveals a role for the centrosome in meiotic recombination.

Author information

1
1] Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain [2] Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb 10000, Croatia.
2
Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain.
3
Departamento de Biología, Edificio de Biológicas, Universidad Autónoma de Madrid, Madrid 28049, Spain.
4
Department of Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University, Mainz 55122, Germany.
5
1] Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain [2] Cytology and Histology Unit, Department of Cell Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallès, Spain.
6
Department of Genetics, St. Jude Children's Research Hospital, Memphis 38105, Tennessee, USA.
7
FIRC Institute of Molecular Oncology, Milan 20139, Italy.

Abstract

CEP63 is a centrosomal protein that facilitates centriole duplication and is regulated by the DNA damage response. Mutations in CEP63 cause Seckel syndrome, a human disease characterized by microcephaly and dwarfism. Here we demonstrate that Cep63-deficient mice recapitulate Seckel syndrome pathology. The attrition of neural progenitor cells involves p53-dependent cell death, and brain size is rescued by the deletion of p53. Cell death is not the result of an aberrant DNA damage response but is triggered by centrosome-based mitotic errors. In addition, Cep63 loss severely impairs meiotic recombination, leading to profound male infertility. Cep63-deficient spermatocytes display numerical and structural centrosome aberrations, chromosome entanglements and defective telomere clustering, suggesting that a reduction in centrosome-mediated chromosome movements underlies recombination failure. Our results provide novel insight into the molecular pathology of microcephaly and establish a role for the centrosome in meiotic recombination.

PMID:
26158450
PMCID:
PMC4499871
DOI:
10.1038/ncomms8676
[Indexed for MEDLINE]
Free PMC Article

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