Aurora Kinase a Phosphorylates BRCA2 to Confer Synthetic Lethality to PARP Inhibitors

BRCA2-deficiency confers synthetic lethality to PARP inhibitors (PARPi) because of the compromised DNA homologous recombination (HR) repair. We previously reported AURKA suppressed BRCA2 expression to control HR. However, the exact mechanism is unclear. Using in vitro kinase assay and mass spectrum analysis, we show phosphorylation of BRCA2 at threonine 10 (T10) by AURKA promotes the interaction between BRCA2 and Skp2, which subsequently induces BRCA2 instability and nuclear proteasome degradation through ubiquitination at lysine 82, whereas the BRCA2-T10A mutant is neither unphosphorylated by AURKA nor degraded by Skp2, but stabilized in nucleus. The non-degradable BRCA2-T10A enhances HR capacity via activation of ATM/Chk2 signaling to induce PARPi resistance. Moreover, SNP rs28897701 (A75P) and rs572782576 (L86P) mutants in BRCA2 interrupt phosphorylation of BRCA2 at T10 by AURKA and consequently induce PARPi resistance. Clinically, AURKA is positively correlated with cytoplasmic pBRCA2 (T10), but negatively correlated with nuclear BRCA2 in ovarian cancer. These data highlight phosphorylation of BRCA2 at T10 by AURKA may be a key event to mediate nuclear degradation and dysfunction of BRCA2, indicating a promising treatment strategy for ovarian cancer or other cancer types with PARPi.Funding Information: This work was supported by grants from the Natural Science Foundation of China (81372797, 82002726, 81572553, 81772789 and 81402153) and the Clinical Postdoctoral Program of Physician Excellence (ZYJH202103). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: All animal experiments were performed in accordance with institutional and international animal regulations. Research involved animal experiments was reviewed and approved by the East China Normal University Institutional Animal Care and Use Committee.