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DNA Damage and Replication Stress Checkpoints

Luke A Yates1,2,3, Xiaodong Zhang1,2, Peter M Burgers4

  • 1DNA Processing Machines Laboratory, Francis Crick Institute, London, United Kingdom.

Annual Review of Biochemistry
|June 20, 2025
PubMed

Insights

DNA damage checkpoints prevent genomic instability and cancer by pausing cell division for DNA repair. This review details the molecular mechanisms of these crucial checkpoints, focusing on ATM and ATR kinases.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • DNA damage checkpoints are essential for maintaining genomic stability.
  • Defects in these checkpoints are linked to cancer development.
  • Understanding checkpoint mechanisms is vital for cancer precision medicine.

Purpose of the Study:

  • To review the current mechanistic understanding of eukaryotic DNA damage checkpoints.
  • To highlight the roles of ATM (Tel1) and ATR (Mec1) sensor kinases.
  • To emphasize structure-function and cellular studies of checkpoint components.

Main Methods:

  • Review of cutting-edge structural techniques.
  • Analysis of molecular insights into checkpoint signaling.
  • Integration of structure-function and cellular studies.

Main Results:

  • Detailed mechanistic understanding of DNA damage checkpoint signaling.
  • Elucidation of the roles of ATM and ATR kinases in response to DNA damage and replication stress.
  • Insights into the coordinated signaling pathways.

Conclusions:

  • DNA damage checkpoints are critical regulators of cell cycle progression.
  • ATM and ATR kinases are key sensors in these pathways.
  • Structural and cellular studies provide a deeper understanding of checkpoint function and its relevance to cancer.
Keywords:
ATMTel1 kinaseATRMec1 kinaseDNA metabolismcell cycle checkpointsreplication stresssignaling cascades

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