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.
Highlights
CEP63 is a centrosomal protein that facilitates centriole duplication and is regulated by the DNA damage response
Many mutations in genes encoding proteins involved in the DNA damage response (DDR) and/or centrosomal functions have been identified in human patients with autosomal recessive primary microcephaly (MCPH) or Seckel syndrome (MCPH accompanied by dwarfism)[1,2,3,4,5,6,7,8,9,10,11,12,13]
Previous work demonstrated an interaction between CEP63 and CEP152, two proteins encoded by established MCPH and Seckel syndrome genes[5,9,22,23]
Summary
CEP63 is a centrosomal protein that facilitates centriole duplication and is regulated by the DNA damage response. Many mutations in genes encoding proteins involved in the DNA damage response (DDR) and/or centrosomal functions have been identified in human patients with autosomal recessive primary microcephaly (MCPH) or Seckel syndrome (MCPH accompanied by dwarfism)[1,2,3,4,5,6,7,8,9,10,11,12,13]. This has suggested that crosstalk between the DDR and the centrosome may be highly relevant to the aetiology of microcephaly. Our results shed light on the complex aetiology of microcephaly and reveal a novel and essential role for centrosomes in promoting recombination during mammalian meiosis
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