AURKA controls oocyte spindle assembly checkpoint and chromosome alignment by HEC1 phosphorylation

Abstract

In human oocytes, meiosis I is error-prone, causing early miscarriages and developmental disorders. The Aurora protein kinases are key regulators of chromosome segregation in mitosis and meiosis and their dysfunction is associated with aneuploidy. Oocytes contain three Aurora kinase (AURK) proteins, but only AURKA is necessary and sufficient to support oocyte meiosis in mice. However, the unique molecular contributions of AURKA remain unclear. Here, using a combination of genetic and pharmacological approaches, we evaluated how AURKA phosphorylation regulates outer kinetochore function during oocyte meiosis. We found that the outer kinetochore protein Ndc80/HEC1 is constitutively phosphorylated at multiple residues by Aurora kinases during meiosis I, but that Serine 69 is specifically phosphorylated by AURKA in mouse and human oocytes. We further show that Serine 69 phosphorylation regulates spindle assembly checkpoint (SAC) activation and chromosome alignment during meiosis I. These results provide a fundamental mechanistic understanding of how AURKA regulates meiosis and kinetochore function to ensure meiosis I fidelity.