Cyclin A2 localises in the cytoplasm at the S/G2 transition to activate PLK1

Life Sci Alliance. 2021 Jan 5;4(3):e202000980. doi: 10.26508/lsa.202000980. Print 2021 Mar.

Abstract

Cyclin A2 is a key regulator of the cell cycle, implicated both in DNA replication and mitotic entry. Cyclin A2 participates in feedback loops that activate mitotic kinases in G2 phase, but why active Cyclin A2-CDK2 during the S phase does not trigger mitotic kinase activation remains unclear. Here, we describe a change in localisation of Cyclin A2 from being only nuclear to both nuclear and cytoplasmic at the S/G2 border. We find that Cyclin A2-CDK2 can activate the mitotic kinase PLK1 through phosphorylation of Bora, and that only cytoplasmic Cyclin A2 interacts with Bora and PLK1. Expression of predominately cytoplasmic Cyclin A2 or phospho-mimicking PLK1 T210D can partially rescue a G2 arrest caused by Cyclin A2 depletion. Cytoplasmic presence of Cyclin A2 is restricted by p21, in particular after DNA damage. Cyclin A2 chromatin association during DNA replication and additional mechanisms contribute to Cyclin A2 localisation change in the G2 phase. We find no evidence that such mechanisms involve G2 feedback loops and suggest that cytoplasmic appearance of Cyclin A2 at the S/G2 transition functions as a trigger for mitotic kinase activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CDC2 Protein Kinase / deficiency
  • CDC2 Protein Kinase / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Nucleus / metabolism
  • Chromatin / metabolism
  • Cyclin A2 / genetics
  • Cyclin A2 / metabolism*
  • Cyclin-Dependent Kinase 2 / deficiency
  • Cyclin-Dependent Kinase 2 / genetics
  • Cytoplasm / metabolism*
  • DNA Damage / genetics
  • Enzyme Activation / genetics
  • G2 Phase / genetics*
  • HeLa Cells
  • Humans
  • Mitosis / genetics
  • Phosphorylation / genetics
  • Protein Binding
  • Protein Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • S Phase / genetics*
  • Signal Transduction / genetics*
  • Transfection

Substances

  • CCNA2 protein, human
  • Cell Cycle Proteins
  • Chromatin
  • Cyclin A2
  • Proto-Oncogene Proteins
  • bora protein, human
  • Protein Serine-Threonine Kinases
  • polo-like kinase 1
  • CDC2 Protein Kinase
  • CDK1 protein, human
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2