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

Marko Marjanović, Carlos Sánchez-Huertas, Berta Terré, Rocío Gómez, Jan Frederik Scheel, Sarai Pacheco, Philip A. Knobel, Ana Martínez-Marchal, Suvi Aivio, Lluís Palenzuela, Uwe Wolfrum, Peter J. McKinnon, José A. Suja, Ignasi Roig, Vincenzo Costanzo (), Jens Lüders () and Travis H. Stracker ()
Additional contact information
Marko Marjanović: Institute for Research in Biomedicine (IRB Barcelona)
Carlos Sánchez-Huertas: Institute for Research in Biomedicine (IRB Barcelona)
Berta Terré: Institute for Research in Biomedicine (IRB Barcelona)
Rocío Gómez: Edificio de Biológicas, Universidad Autónoma de Madrid
Jan Frederik Scheel: Institute of Zoology, Johannes Gutenberg University
Sarai Pacheco: Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona
Philip A. Knobel: Institute for Research in Biomedicine (IRB Barcelona)
Ana Martínez-Marchal: Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona
Suvi Aivio: Institute for Research in Biomedicine (IRB Barcelona)
Lluís Palenzuela: Institute for Research in Biomedicine (IRB Barcelona)
Uwe Wolfrum: Institute of Zoology, Johannes Gutenberg University
Peter J. McKinnon: St. Jude Children’s Research Hospital
José A. Suja: Edificio de Biológicas, Universidad Autónoma de Madrid
Ignasi Roig: Genome Integrity and Instability Group, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona
Vincenzo Costanzo: FIRC Institute of Molecular Oncology
Jens Lüders: Institute for Research in Biomedicine (IRB Barcelona)
Travis H. Stracker: Institute for Research in Biomedicine (IRB Barcelona)

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8676

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