title: Aurora-A controls pre-replicative complex assembly and DNA replication by stabilizing geminin in mitosis.
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 SCF(Skp2)-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.
authors.affiliation: Department of Oral and Maxillofacial Pathobiology, Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
authors.forename: Takaaki
authors.initials: T
authors.lastname: Tsunematsu
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Takihara
authors.forename: Naozumi
authors.initials: N
authors.lastname: Ishimaru
authors.forename: Michele
authors.initials: M
authors.lastname: Pagano
authors.forename: Takashi
authors.initials: T
authors.lastname: Takata
authors.forename: Yasusei
authors.initials: Y
authors.lastname: Kudo
mesh_terms: D000595:Amino Acid Sequence; D064173:Anaphase-Promoting Complex-Cyclosome / Q000378:metabolism; D064096:Aurora Kinase A / Q000737:chemistry / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D004261:DNA Replication; D015536:Down-Regulation; D064248:Geminin / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008938:Mitosis; D008969:Molecular Sequence Data; D010766:Phosphorylation; D010769:Phosphothreonine / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D059748:Proteolysis; D012995:Solubility
chemical_list: C467199:CDT1 protein, human; D018797:Cell Cycle Proteins; D064248:Geminin; D010769:Phosphothreonine; D064173:Anaphase-Promoting Complex-Cyclosome; C576917:AURKA protein, human; D064096:Aurora Kinase A; D046988:Proteasome Endopeptidase Complex