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Regulation of DNA replication by the S-phase DNA damage checkpoint

Nicholas Willis1, Nicholas Rhind

  • 1Biochemistry and Molecular Pharmacology, University on Massachusetts Medical School, Worcester MA 01605, USA. nick.rhind@umassmed.edu.

Cell Division
|July 7, 2009
PubMed

Insights

Cells slow DNA replication upon damage via two mechanisms: inhibiting origin firing and slowing replication forks. This review clarifies their roles in DNA damage response, highlighting ATM

Area of Science:

  • Cellular response to DNA damage
  • DNA replication regulation
  • Cell cycle checkpoints

Background:

  • Cellular replication slows in response to DNA damage, a phenomenon linked to the discovery of ATM.
  • The precise mechanisms by which S-phase DNA damage checkpoints impede replication remain incompletely understood.
  • Conflicting data exists regarding the relative importance of inhibiting origin firing versus slowing replication fork progression.

Purpose of the Study:

  • To review and synthesize current knowledge on how cells slow replication following DNA damage.
  • To resolve discrepancies in the literature regarding the roles of origin firing inhibition and fork slowing.
  • To propose a model differentiating global and local checkpoint mechanisms.

Main Methods:

  • Literature review of studies on DNA damage checkpoints and replication.
  • Analysis of conflicting experimental results across different systems and damaging agents.
  • Synthesis of findings to propose a unified mechanistic model.

Main Results:

  • Both inhibition of replication origin firing and slowing of replication fork progression contribute to replication stress response.
  • Origin firing inhibition acts as a global checkpoint mechanism, reducing overall DNA synthesis.
  • Fork slowing is a local mechanism, impacting replisomes encountering DNA damage.

Conclusions:

  • Replication origin firing inhibition is a global response to DNA damage checkpoints.
  • Replication fork slowing is a localized response, significant at high lesion densities.
  • This dual mechanism ensures genome stability during DNA damage.

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