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

Nat Commun. 2013:4:1885. doi: 10.1038/ncomms2859.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Anaphase-Promoting Complex-Cyclosome / metabolism
  • Aurora Kinase A / chemistry
  • Aurora Kinase A / metabolism*
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • DNA Replication*
  • Down-Regulation
  • Geminin / chemistry
  • Geminin / metabolism*
  • Humans
  • Mitosis*
  • Molecular Sequence Data
  • Phosphorylation
  • Phosphothreonine / metabolism
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Stability
  • Proteolysis
  • Solubility

Substances

  • CDT1 protein, human
  • Cell Cycle Proteins
  • Geminin
  • Phosphothreonine
  • Anaphase-Promoting Complex-Cyclosome
  • AURKA protein, human
  • Aurora Kinase A
  • Proteasome Endopeptidase Complex