title: Aurora-A expressing tumour cells are deficient for homology-directed DNA double strand-break repair and sensitive to PARP inhibition.
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.
authors.affiliation: The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK. tony.sourisseau@icr.ac.uk
authors.forename: Tony
authors.initials: T
authors.lastname: Sourisseau
authors.forename: Despina
authors.initials: D
authors.lastname: Maniotis
authors.forename: Afshan
authors.initials: A
authors.lastname: McCarthy
authors.forename: Chan
authors.initials: C
authors.lastname: Tang
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Lord
authors.forename: Alan
authors.initials: A
authors.lastname: Ashworth
authors.forename: Spiros
authors.initials: S
authors.lastname: Linardopoulos
mesh_terms: D064127:Aurora Kinases; D002453:Cell Cycle; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D006801:Humans; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency*; D051135:Rad51 Recombinase / Q000378:metabolism*
chemical_list: D011065:Poly(ADP-ribose) Polymerases; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; C495153:RAD51 protein, human; D051135:Rad51 Recombinase