ARK1

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Introduction

Aurora kinases (AURKA) were first discovered in budding yeast in 1993. The AURKA orthologue in Saccharomyces cerevisiae is a protein called Ipl1 (increase-in-ploidy 1), which has been verified as a mitotic factor that controls chromosome segregation. Later, two Ipl1 orthologues were found in Xenopus laevis and Drosophila melanogaster. In these two organisms, Ipl1 orthologues are kinases that have multiple roles in mitosis, including regulating centrosomal stability and constructing and maintaining mitotic spindle. These roles are shared by the three mammalian orthologues of Ipl1 are called Aurora kinases (AURKA, AURKB and AURKC), and they are overexpressed in several solid tumors including breast cancer, skin cancer, pancreatic cancer, and ovarian cancer. And the amplification of the AURKA gene which is located on chromosome 20p13 was found in some hematological malignancies and epithelial cancers. Many studies have shown that the overexpression of AURKA is closely related to malignant tumors, with poor outcomes and low survival rates. Due to a large amount of evidence showing the clinical relevance of this protein, people began to make great efforts to understand the molecular function of AURKA in cell division. Nowadays, more and more studies show that AURKA has both mitotic and non-mitotic effects. With the increasing sensitivity of microscope tools and the application of a variety of cutting-edge technologies, scientists have also discovered new functions of AURKA in different subcellular compartments.

Emerging roles of AURKA outside mitosis

A large amount of impressive evidence shows that the massive accumulation of AURKA at centrosomes begins in the late G2 stage and continues throughout the entire M stage, where the kinase locates on the mitotic spindle, to the midzone and the midbody. Once mitosis is achieved, AURKA's mitotic pool is dismantled and the protein is degraded at the midbody.

For this reason, AURKA is targeted by the E3 ubiquitin-protein ligase machinery, the anaphase-promoting complex/cyclosome and its two co-activator subunits CDC20 and CDH1. Although consensus has been reached on the degradation of AURKA after mitosis, whether the process is ubiquitin-dependent or independent is still a controversial issue. On the one hand, E3 ubiquitin protein ligase CHFR binds to the N-terminal region of AURKA and ubiquitinates the kinase, delivering AURKA to the proteasome for degradation. On the other hand, studies in cell culture models have shown that Aurora A kinase interacting protein 1 (AURKAIP1) enhances the binding of Antizyme1 (AZ1) on AURKA. AZ1 is an enzyme belonging to the pathway of polyamine biosynthesis, which is known to regulate ubiquitin-independent protein degradation programs. According to its enzymatic function, AZ1 promotes the ubiquitin-independent but proteasome-dependent degradation of AURKA after mitotic exit. Nowadays, there are still many unknown issues. For example, when discussing the non-mitotic effects of AURKA, should tissue specificity be considered? Are there new physiological non-mitotic effects of AURKA that have not yet been discovered? We look forward to the development of microscope functions and high-throughput technology to help answer these questions.

AURKA participates in DNA repair and gene transcription

In addition to its physiological effects in cell division, studies have also reported the non-mitotic effects of AURKA in cancer cells. Samples of urothelial cell carcinoma derived from patients showed that the overexpression of AURKA is negatively correlated with the expression of DNA damage response genes BRCA1 and CHK2. A recent study pointed out a new role of AURKA in regulating the activity of poly (ADP-ribose) 1 (PARP1). Inhibition of AURKA in ovarian cancer cells has been shown to reduce PARP1 levels and promote non-homologous end joining repair (NHEJ) mechanisms. The NHEJ mechanisms are error-prone and may cause cytotoxicity and cell death. The induction of NHEJ by the AURKA inhibitor Alisertib reduces the growth and survival rate of ovarian cancer cells. This work allows re-examining the role of AURKA in DNA repair from a non-mitotic perspective. Interestingly, the function of AURKA in the nucleus does not depend on the kinase activity of AURKA, but only requires the nuclear localization of the kinase. It also shows that the transcriptional activation of MYC by AURKA is unrelated to the mitotic effect of kinases, which further proves that the spatiotemporal localization of AURKA outside mitosis greatly affects its carcinogenicity. A recent report pointed out that nuclear AURKA acts as a transcription enhancer in breast cancer stem cells, so it will be interesting and important to monitor whether nuclear AURKA induces cancer stem cell phenotypes in different populations of cancer stem cells.

Figure 1. Schematic overview of the non-mitotic roles of AURKA with relevance for cancer (Bertolin, G.; Tramier, M. 2019)