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A novel replication arrest pathway in response to DNA damage

Matthew P Stokes1, W Matthew Michael

  • 1Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts, USA.

Cell Cycle (Georgetown, Tex.)
|January 9, 2004
PubMed

Insights

DNA damage creates a diffusible inhibitor that blocks replication initiation by preventing PCNA loading onto undamaged DNA. This novel pathway amplifies checkpoint activation, stopping cell cycle progression even with low DNA damage levels.

Area of Science:

  • Molecular Biology
  • Cell Cycle Regulation
  • DNA Replication

Background:

  • DNA damage typically regulates replication by inhibiting origin use and slowing progression.
  • A previously reported mechanism involves DNA damage inhibiting chromosomal replication initiation in trans.

Purpose of the Study:

  • To elucidate a novel mechanism by which DNA damage inhibits replication initiation.
  • To investigate the role of PCNA loading in DNA damage-induced replication control.

Main Methods:

  • Analysis of DNA damage effects on replication initiation.
  • Investigation of the interaction between DNA damage and replication factors.
  • Characterization of the inhibitory mechanism and its relation to checkpoint signaling.

Main Results:

  • DNA damage generates a diffusible inhibitor that blocks the association of PCNA with undamaged chromatin.
  • This inhibition of PCNA loading is independent of canonical checkpoint signaling.
  • The pathway leads to checkpoint activation, suggesting an amplification role.

Conclusions:

  • DNA damage can inhibit replication initiation via a novel pathway involving a diffusible inhibitor of PCNA loading.
  • This mechanism acts in trans and is independent of canonical checkpoint signaling.
  • This pathway may amplify cell cycle arrest in response to DNA damage.

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