title: CEP63 deficiency promotes p53-dependent microcephaly and reveals a role for the centrosome in meiotic recombination.
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.
authors.affiliation: 1] Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain [2] Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb 10000, Croatia.
authors.forename: Marko
authors.initials: M
authors.lastname: Marjanović
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain.
authors.forename: Carlos
authors.initials: C
authors.lastname: Sánchez-Huertas
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain.
authors.forename: Berta
authors.initials: B
authors.lastname: Terré
authors.affiliation: Departamento de Biología, Edificio de Biológicas, Universidad Autónoma de Madrid, Madrid 28049, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Gómez
authors.affiliation: Department of Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University, Mainz 55122, Germany.
authors.forename: Jan Frederik
authors.initials: JF
authors.lastname: Scheel
authors.affiliation: 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.
authors.forename: Sarai
authors.initials: S
authors.lastname: Pacheco
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Knobel
authors.affiliation: 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.
authors.forename: Ana
authors.initials: A
authors.lastname: Martínez-Marchal
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain.
authors.forename: Suvi
authors.initials: S
authors.lastname: Aivio
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain.
authors.forename: Lluís
authors.initials: L
authors.lastname: Palenzuela
authors.affiliation: Department of Cell and Matrix Biology, Institute of Zoology, Johannes Gutenberg University, Mainz 55122, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Wolfrum
authors.affiliation: Department of Genetics, St. Jude Children's Research Hospital, Memphis 38105, Tennessee, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McKinnon
authors.affiliation: Departamento de Biología, Edificio de Biológicas, Universidad Autónoma de Madrid, Madrid 28049, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Suja
authors.affiliation: 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.
authors.forename: Ignasi
authors.initials: I
authors.lastname: Roig
authors.affiliation: FIRC Institute of Molecular Oncology, Milan 20139, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Costanzo
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain.
authors.forename: Jens
authors.initials: J
authors.lastname: Lüders
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Barcelona 08028, Spain.
authors.forename: Travis H
authors.initials: TH
authors.lastname: Stracker
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D018385:Centrosome / Q000378:metabolism*; D004249:DNA Damage; D004392:Dwarfism / Q000235:genetics*; D019066:Facies; D059765:Homologous Recombination / Q000235:genetics*; D007150:Immunohistochemistry; D008297:Male; D008540:Meiosis / Q000235:genetics*; D051379:Mice; D008831:Microcephaly / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D011995:Recombination, Genetic / Q000235:genetics; D013076:Sperm Count; D013090:Spermatocytes / Q000378:metabolism* / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; C586106:Cep63 protein, mouse; D016159:Tumor Suppressor Protein p53