Cell Cycle-Dependent Switch of TopBP1 Functions by Cdk2 and Akt

Mol Cell Biol. 2020 Mar 30;40(8):e00599-19. doi: 10.1128/MCB.00599-19. Print 2020 Mar 30.


Cdk2-dependent TopBP1-treslin interaction is critical for DNA replication initiation. However, it remains unclear how this association is terminated after replication initiation is finished. Here, we demonstrate that phosphorylation of TopBP1 by Akt coincides with cyclin A activation during S and G2 phases and switches the TopBP1-interacting partner from treslin to E2F1, which results in the termination of replication initiation. Premature activation of Akt in G1 phase causes an early switch and inhibits DNA replication. TopBP1 is often overexpressed in cancer and can bypass control by Cdk2 to interact with treslin, leading to enhanced DNA replication. Consistent with this notion, reducing the levels of TopBP1 in cancer cells restores sensitivity to a Cdk2 inhibitor. Together, our study links Cdk2 and Akt pathways to the control of DNA replication through the regulation of TopBP1-treslin interaction. These data also suggest an important role for TopBP1 in driving abnormal DNA replication in cancer.

Keywords: Akt; Cdk2; TopBP1; cyclin A; treslin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Cycle / physiology
  • Cell Cycle Checkpoints / physiology
  • Cell Cycle Proteins / metabolism
  • Cell Division / physiology
  • Cell Line
  • Cyclin-Dependent Kinase 2 / genetics
  • Cyclin-Dependent Kinase 2 / metabolism*
  • Cyclins / genetics
  • DNA Replication / physiology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • G2 Phase / physiology
  • Humans
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphorylation
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism*
  • S Phase / physiology


  • Carrier Proteins
  • Cell Cycle Proteins
  • Cyclins
  • DNA-Binding Proteins
  • Nuclear Proteins
  • TOPBP1 protein, human
  • Proto-Oncogene Proteins c-akt
  • CDK2 protein, human
  • Cyclin-Dependent Kinase 2