Abstract
The catalytic activity of human AURORA-A kinase (AURKA) regulates mitotic progression, and its frequent overexpression in major forms of epithelial cancer is associated with aneuploidy and carcinogenesis. Here, we report an unexpected, kinase-independent function for AURKA in DNA replication initiation whose inhibition through a class of allosteric inhibitors opens avenues for cancer therapy. We show that genetic depletion of AURKA, or its inhibition by allosteric but not catalytic inhibitors, blocks the G1-S cell cycle transition. A catalytically inactive AURKA mutant suffices to overcome this block. We identify a multiprotein complex between AURKA and the replisome components MCM7, WDHD1 and POLD1 formed during G1, and demonstrate that allosteric but not catalytic inhibitors prevent the chromatin assembly of functional replisomes. Indeed, allosteric but not catalytic AURKA inhibitors sensitize cancer cells to inhibition of the CDC7 kinase subunit of the replication-initiating factor DDK. Thus, our findings define a mechanism essential for replisome assembly during DNA replication initiation that is vulnerable to inhibition as combination therapy in cancer.
Highlights
Human cancers originating in many different tissues frequently amplify or overexpress the AURORA-A kinase (AURKA) gene [1,2,3], but how the 403 amino acid protein kinase encoded by the gene promotes carcinogenesis remains unclear
AURKA interacts with the mitotic protein TPX2, inducing an allosteric change that activates kinase catalytic activity, which is blocked by small-molecule inhibitors of the AURKA/TPX2 interaction [22,23,24]
Allosteric but not catalytic AURKA inhibitors provoke cell cycle arrest in interphase We first examined the cell cycle profile of cells treated with ATP-competitive (MLN8237 or VX-689) [3,30,31,32,33] or allosteric (CD532) inhibitors of AURKA [25,34,35,36,37,38]
Summary
Human cancers originating in many different tissues frequently amplify or overexpress the AURKA gene [1,2,3], but how the 403 amino acid protein kinase encoded by the gene promotes carcinogenesis remains unclear. We demonstrate that AURKA is necessary for the assembly of functional replisomes during the G1-S phase transition, and that allosteric but not catalytic inhibitors prevent the chromatin loading of replication factors required for the efficient initiation of DNA replication.
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