The gene encoding the Aurora-A protein kinase is located in the 20q13 breast cancer amplicon and is also overexpressed in colorectal, pancreatic and gastric tumours. Although Aurora-A may not be a bona fide oncoprotein in humans, it is a promising drug target in cancer therapy. Thus, it is surprising that so little is known of its role in normal cells. The primary function of Aurora-A is to promote bipolar spindle assembly, but the molecular details of this process remained obscure until recently. The discovery of several novel Aurora-A-binding proteins and substrates has implicated Aurora-A in centrosome maturation and separation, acentrosomal and centrosomal spindle assembly, kinetochore function, cytokinesis and in cell fate determination. Here we discuss recent advances in determining the early mitotic role of Aurora-A, with a strong emphasis on its function at the mitotic spindle poles.
Following DNA damage caused by exogenous sources, such as ionizing radiation, the tumour suppressor p53 mediates cell cycle arrest via expression of the CDK inhibitor, p21. However, the role of p21 in maintaining genomic stability in the absence of exogenous DNA-damaging agents is unclear. Here, using live single-cell measurements of p21 protein in proliferating cultures, we show that naturally occurring DNA damage incurred over S-phase causes p53-dependent accumulation of p21 during mother G2- and daughter G1-phases. High p21 levels mediate G1 arrest via CDK inhibition, yet lower levels have no impact on G1 progression, and the ubiquitin ligases CRL4Cdt2 and SCFSkp2 couple to degrade p21 prior to the G1/S transition. Mathematical modelling reveals that a bistable switch, created by CRL4Cdt2, promotes irreversible S-phase entry by keeping p21 levels low, preventing premature S-phase exit upon DNA damage. Thus, we characterize how p21 regulates the proliferation-quiescence decision to maintain genomic stability.
Autosomal recessive primary microcephaly (MCPH) is characterised by a significant reduction in prenatal human brain growth, without alteration of cerebral architecture. The genetic aetiology of MCPH is bi-allelic mutations in genes coding for a subset of centrosomal proteins1-10. While at least three of these proteins have been implicated in centrosome duplication11, the nature of centrosome dysfunction that underlies the neurodevelopmental defect in MCPH is unclear. Here we report a homozygous MCPH-causing mutation in the human CEP63 gene. CEP63 forms a complex with another MCPH protein, CEP152, a conserved centrosome duplication factor12-15. Together, they are essential for maintaining normal centrosome numbers in cells. Using super-resolution microscopy we find that CEP63 and CEP152 co-localise in a discrete ring around the proximal end of the parental centriole, a pattern specifically disrupted in CEP63-deficient patient-derived cells. This work suggests that the CEP152-CEP63 ring-like structure ensures normal neurodevelopment and its impairment particularly affects human cerebral cortex growth.
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