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.
|Titolo:||CEP63 deficiency promotes p53-dependent microcephaly and reveals a role for the centrosome in meiotic recombination|
COSTANZO, VINCENZO [Supervision] (Corresponding)
|Parole Chiave:||Animals; Cell Cycle Proteins; Centrosome; DNA Damage; Dwarfism; Facies; Homologous Recombination; Immunohistochemistry; Male; Meiosis; Mice; Microcephaly; Real-Time Polymerase Chain Reaction; Recombination, Genetic; Sperm Count; Spermatocytes; Tumor Suppressor Protein p53|
|Settore Scientifico Disciplinare:||Settore MED/04 - Patologia Generale|
|Data di pubblicazione:||9-lug-2015|
|Digital Object Identifier (DOI):||10.1038/ncomms8676|
|Appare nelle tipologie:||01 - Articolo su periodico|