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ATR pathway is the primary pathway for activating G2/M checkpoint induction after re-replication

Jie Jessie Lin1, Anindya Dutta

  • 1Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia 22908, USA.

The Journal of Biological Chemistry
|August 25, 2007
PubMed

Insights

Geminin inactivation causes DNA re-replication in tumor cells, activating the ATR/Chk1 pathway for early cell cycle arrest. The ATM/Chk2 pathway is activated later as a consequence of this re-replication.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • DNA replication requires precise control to ensure genomic stability.
  • Geminin is a key inhibitor of DNA replication origin licensing.
  • Loss of Geminin can lead to uncontrolled DNA re-replication and genomic instability in cancer cells.

Purpose of the Study:

  • To investigate the signaling pathways involved in detecting and responding to DNA re-replication.
  • To elucidate the roles of ATR and ATM kinases in the checkpoint response to Geminin inactivation.

Main Methods:

  • Human tumor cells with Geminin inactivation were analyzed.
  • Activation of checkpoint kinases (ATR, ATM, Chk1, Chk2) and associated protein complexes (9-1-1 clamp, Mre11-Rad50-Nbs1) were assessed.

Main Results:

  • ATR kinase and the 9-1-1 clamp complex, with Rad17-RFC, are the primary sensors of DNA re-replication upon Geminin loss.
  • Chk1 activation is early, while Chk2 activation is delayed, suggesting distinct pathway kinetics.
  • ATM kinase and the Mre11-Rad50-Nbs1 complex play minor roles in this specific checkpoint response.

Conclusions:

  • The ATR/Chk1 pathway is crucial for early checkpoint arrest following Geminin inactivation, preventing further cell cycle progression.
  • ATM/Chk2 pathway activation is a later event, likely a consequence of ongoing DNA re-replication, rather than an initial trigger.

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