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Aurora-A controls pre-replicative complex assembly and DNA replication by stabilizing geminin in mitosis

Author

Listed:
  • Takaaki Tsunematsu

    (Graduate School of Biomedical and Health Sciences, Hiroshima University)

  • Yoshihiro Takihara

    (Research Institute for Radiation Biology and Medicine, Hiroshima University)

  • Naozumi Ishimaru

    (Institute of Health Biosciences, University of Tokushima Graduate School)

  • Michele Pagano

    (New York University Cancer Institute, New York University School of Medicine
    Howard Hughes Medical Institute)

  • Takashi Takata

    (Graduate School of Biomedical and Health Sciences, Hiroshima University)

  • Yasusei Kudo

    (Graduate School of Biomedical and Health Sciences, Hiroshima University
    Institute of Health Biosciences, University of Tokushima Graduate School)

Abstract

Geminin, an essential factor for DNA replication, directly binds to the licensing factor Cdt1 and inhibits pre-replicative complex formation to prevent re-replication. In G1, geminin levels are controlled by the anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase complex, which targets geminin for proteasomal degradation to allow pre-replicative complex formation. Conversely, from S to G2, geminin is stabilized due to APC/C ubiquitin ligase complex inhibition, ensuring the inhibition of pre-replicative complex formation. However, mitotic regulation of geminin has hitherto not been described. Here we show that Aurora-A phosphorylates geminin on Thr25 during M phase, and this event induces geminin stabilization by preventing its APC/C ubiquitin ligase complex-mediated degradation during mitosis. In turn, stabilized geminin inhibits SCFSkp2-mediated degradation of Cdt1 to ensure pre-replicative complex formation in the ensuing S phase. The Aurora-A–geminin–Cdt1 axis therefore represents a critical regulator of proper DNA replication.

Suggested Citation

  • Takaaki Tsunematsu & Yoshihiro Takihara & Naozumi Ishimaru & Michele Pagano & Takashi Takata & Yasusei Kudo, 2013. "Aurora-A controls pre-replicative complex assembly and DNA replication by stabilizing geminin in mitosis," Nature Communications, Nature, vol. 4(1), pages 1-11, October.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms2859
    DOI: 10.1038/ncomms2859
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    Cited by:

    1. Ji Min Lee & Henrik M. Hammarén & Mikhail M. Savitski & Sung Hee Baek, 2023. "Control of protein stability by post-translational modifications," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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