Brown, N.J.; (2012) Characterisation of the centrosome protein Cep63. Doctoral thesis , UCL (University College London).

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Abstract

In dividing cells, centrosomes act as the primary microtubule organising centre to orchestrate mitotic spindle assembly. Bipolar spindle assembly is responsible for accurate segregation of sister chromatids, such that each daughter cell receives an identical copy of the genome. Changes in centrosome number can lead to a lack of mitotic fidelity and genome instability. Chromosomes are replicated in a controlled and timely fashion and the same is true for centrosomes so that cells enter mitosis with two centrosomes. Further to their role in spindle assembly, centrosomes are also important in cell cycle regulation and DNA damage checkpoint signalling. Centrosomes are particularly important in the regulation of neuroepithelial cell division in the developing brain: all known incidences of primary microcephaly are caused by mutations in centrosome or spindle pole proteins. Xenopus laevis Cep63 is a target of DNA damage kinase, ATM, and it’s important for the formation of bipolar mitotic spindles (Smith et al., 2009). Therefore, Cep63 is an exciting candidate for maintenance of genome stability. Human Cep63 has been identified as a centrosome protein (Andersen et al., 2003), but its function was uncharacterised. In this thesis Cep63 was shown to be a constitutive centrosome protein, which plays a role in the regulation of centriole duplication. Cep152 was identified as a Cep63 interacting protein; and Cep63 and Cep152 are dependent on each other for their centrosomal localisation. Cep152 is required for centriole duplication via recruitment of essential duplication factors, Plk4 and CPAP, to the centrosome (Dzhindzhev et al., 2010b, Cizmecioglu et al., 2010, Hatch et al., 2010b). Furthermore, mouse embryonic fibroblasts in which the Cep63 gene is disrupted show decreased centriole numbers and signs of genome instability. Intriguingly, preliminary analysis of mouse embryos points to a potential link between Cep63 deficiency and microcephaly. We propose that Cep63 and Cep152 function together to ensure correct centrosomal levels of the essential centriole duplication factors Plk4 and CPAP.

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