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

Takaaki Tsunematsu, Yoshihiro Takihara, Naozumi Ishimaru, Michele Pagano, Takashi Takata and Yasusei Kudo ()
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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
Takashi Takata: Graduate School of Biomedical and Health Sciences, Hiroshima University
Yasusei Kudo: Graduate School of Biomedical and Health Sciences, Hiroshima University

Nature Communications, 2013, vol. 4, issue 1, 1-11

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms2859

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