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MCPH1/BRIT1 limits ionizing radiation-induced centrosome amplification

Oncogene volume 29, pages 5537–5544 (2010)Cite this article

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Abstract

Microcephalin (MCPH1/BRIT1) is a potential tumour suppressor that localizes to the centrosome, forms ionizing radiation-induced nuclear foci (IRIF) and is involved in the DNA damage checkpoints that ensure genome stability. Here, we report the impact of Mcph1 disruption in the hyper-recombinogenic DT40 cell line. Mcph1−/− cells were viable and proliferated at the same rate as wild-type controls. Mcph1-deficient cells had intact G2-to-M checkpoint responses after ionizing radiation (IR) treatment, but showed moderate radiosensitivity. Light and electron microscopy indicated normal centrosome structures in Mcph1 null cells, but IR induced massive amplification of centrosome numbers in the absence of Mcph1. Mcph1 null cells formed γ-H2AX and Rad51 IRIF, but resolved them more slowly than wild-type cells. Mcph1 deficiency caused sustained Chk1 phosphorylation after IR, dysregulating Cdk2 activity. These findings show that Mcph1 controls centrosome numbers after DNA damage, which may indicate a novel tumour suppressive mechanism for microcephalin.

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Acknowledgements

We thank William Tsang and Brian Dynlacht for the Cep76 antibody, Andrew Jackson and Andrea Robertson for the MCPH1 mutant lymphoblastoid cells, Tiago Dantas for help with the EM and Noel Lowndes for critical reading of the paper. CL was funded by the National Biophotonics and Imaging Platform funded by the HEA under PRTLI4. This work was supported by the Health Research Board project grant RP/2006/36 and Science Foundation Ireland Principal Investigator award 08/IN.1/B1029.

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  1. J A L Brown and E Bourke: These authors contributed equally to this work and should be considered joint first authors.

Authors and Affiliations

  1. Centre for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, Galway, Ireland

    J A L Brown, E Bourke & C G Morrison

  2. School of Medicine, National University of Ireland Galway, Galway, Ireland

    C Liptrot & P Dockery

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  1. J A L Brown
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Correspondence to C G Morrison.

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Brown, J., Bourke, E., Liptrot, C. et al. MCPH1/BRIT1 limits ionizing radiation-induced centrosome amplification. Oncogene 29, 5537–5544 (2010). https://doi.org/10.1038/onc.2010.302

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