Distinct roles for cyclins E and A during DNA replication complex assembly and activation

Nat Cell Biol. 2002 Jul;4(7):523-8. doi: 10.1038/ncb813.

Abstract

Initiation of DNA replication is regulated by cyclin-dependent protein kinase 2 (Cdk2) in association with two different regulatory subunits, cyclin A and cyclin E (reviewed in ref. 1). But why two different cyclins are required and why their order of activation is tightly regulated are unknown. Using a cell-free system for initiation of DNA replication that is based on G1 nuclei, G1 cytosol and recombinant proteins, we find that cyclins E and A have specialized roles during the transition from G0 to S phase. Cyclin E stimulates replication complex assembly by cooperating with Cdc6, to make G1 nuclei competent to replicate in vitro. Cyclin A has two separable functions: it activates DNA synthesis by replication complexes that are already assembled, and it inhibits the assembly of new complexes. Thus, cyclin E opens a 'window of opportunity' for replication complex assembly that is closed by cyclin A. The dual functions of cyclin A ensure that the assembly phase (G1) ends before DNA synthesis (S) begins, thereby preventing re-initiation until the next cell cycle.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / metabolism
  • Cell-Free System
  • Cyclin A / physiology*
  • Cyclin E / physiology*
  • DNA Replication*
  • G1 Phase
  • Humans
  • Nuclear Proteins / metabolism
  • Phosphorylation

Substances

  • CDC6 protein, human
  • Cell Cycle Proteins
  • Cyclin A
  • Cyclin E
  • Nuclear Proteins