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, Travis H. Stracker

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Abstract

© 2015 Macmillan Publishers Limited. All rights reserved. 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.
Original languageEnglish
Article number8676
JournalNature Communications
Volume6
DOIs
Publication statusPublished - 9 Jul 2015

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    Marjanović, M., Sánchez-Huertas, C., Terré, B., Gómez, R., Scheel, J. F., Pacheco, S., Knobel, P. A., Martínez-Marchal, A., Aivio, S., Palenzuela, L., Wolfrum, U., McKinnon, P. J., Suja, J. A., Roig, I., Costanzo, V., Lüders, J., & Stracker, T. H. (2015). CEP63 deficiency promotes p53-dependent microcephaly and reveals a role for the centrosome in meiotic recombination. Nature Communications, 6, [8676]. https://doi.org/10.1038/ncomms8676