Abstract
The protein kinase Aurora-A is a major regulator of the cell cycle that orchestrates mitotic entry and is required for the assembly of a functional mitotic spindle. Overexpression of Aurora-A has been strongly linked with oncogenesis and this has led to considerable efforts at therapeutic targeting of the kinase activity of this protein. However, the exact mechanism by which Aurora-A promotes oncogenesis remains unclear. Here, we show that Aurora-A modulates the repair of DNA double-strand breaks (DSBs). Aurora-A expression inhibits RAD51 recruitment to DNA DSBs, decreases DSB repair by homologous recombination and sensitizes cancer cells to PARP inhibition. This impairment of RAD51 function requires inhibition of CHK1 by Polo-like kinase 1 (PLK1). These results identify a novel function of Aurora-A in modulating the response to DNA DSB that likely contributes to carcinogenesis and suggest a novel therapeutic approach to the treatment of cancers overexpressing this protein.
Highlights
Aurora-A is a centrosome-associated, cell cycle-regulated member of the Aurora serine/threonine protein kinase family which is important for mitosis (Bischoff & Plowman, 1999; Carmena & Earnshaw, 2003; Giet & Prigent, 1999; Nigg, 2001)
Aurora-A overexpression impairs RAD51 focus formation To assess the potential effect of Aurora-A on homologous recombination (HR), we examined the formation of nuclear RAD51 foci after DNA damage
The localization of these foci after damage most likely represents the loading of the RAD51 DNA recombinase onto damaged DNA, an essential part of the HR process known to be controlled by other HR proteins, such as BRCA1 and BRCA2 (West, 2003)
Summary
Aurora-A is a centrosome-associated, cell cycle-regulated member of the Aurora serine/threonine protein kinase family which is important for mitosis (Bischoff & Plowman, 1999; Carmena & Earnshaw, 2003; Giet & Prigent, 1999; Nigg, 2001). The protein level and activity of Aurora-A peaks at G2 and during mitosis whereas expression is low in resting cells (Sasai et al, 2008; Zhou et al, 1998). Aurora-A is essential for multiple processes during mitosis, including mitotic spindle formation and activation of cell cycle regulators such as PLK1 and CDK1 (Cazales et al, 2005; Seki et al, 2008). Perhaps unsurprisingly, targeting Aurora-A (1) The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK. (2) Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, UK.
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