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

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

NF-κB Induction of the SUMO Protease SENP2: A Negative Feedback Loop to Attenuate Cell Survival Response to Genotoxic Stress

Activation of NF-κB, pivotal for immunity and oncogenesis, is tightly controlled by multiple feedback mechanisms. In response to DNA damage, SUMOylation of NEMO (NF-κB essential modulator) is critical for NF-κB activation, however SUMO proteases and feedback mechanisms involved remain unknown. Here we show that among the six known SENPs (Sentrin/SUMO-specific proteases) only SENP2 can efficiently associate with NEMO, deSUMOylate NEMO and inhibit NF-κB activation induced by DNA damage. We further show that NF-κB induces SENP2 (and SENP1) transcription selectively in response to genotoxic stimuli, which involves ATM (ataxia telangiectasia mutated)-dependent histone methylation of SENP2 promoter κB regions and NF-κB recruitment. SENP2-null cells display biphasic NEMO SUMOylation and activation of IKK and NF-κB, and higher resistance to DNA damage-induced cell death. Our study establishes a self-attenuating feedback mechanism selective to DNA damage induced signaling to limit NF-κB-dependent cell survival responses