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Roles of ATM and ATR in DNA double strand breaks and replication stress

Rhys M Williams1, Xiaodong Zhang1

  • 1Section of Structural and Synthetic Biology, Department of Infectious Disease, Imperial College London, London, SW7 2AZ, UK.

Progress in Biophysics and Molecular Biology
|December 1, 2020
PubMed

Insights

Genome integrity is maintained by ATM and ATR kinases, which respond differently to DNA damage and replication stress. Controlling their localization orchestrates stress-specific repair pathways.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Genome integrity is essential for cell division and preventing DNA damage accumulation, which can lead to cancer.
  • ATM (Ataxia-Telangiectasia Mutated) and ATR (Ataxia-Telangiectasia and Rad3-Related) are key kinases involved in DNA repair.
  • These kinases play crucial roles in homologous recombination repair of double-strand breaks and managing replication stress.

Purpose of the Study:

  • To review the current understanding of ATM and ATR kinase roles in DNA damage and replication stress responses.
  • To elucidate the mechanisms of ATM and ATR recruitment, activation, and activity.
  • To discuss how the spatial control of these kinases and their activators enables stress-specific cellular responses.

Main Methods:

  • Literature review of studies on ATM and ATR signaling pathways.
  • Analysis of molecular mechanisms governing kinase recruitment and activation.
  • Discussion of the role of subcellular localization in DNA damage response.

Main Results:

  • ATM and ATR are master kinases critical for genome stability.
  • Their functions are intertwined in double-strand break repair but diverge during replication stress.
  • Localization of ATM/ATR and their activators dictates specific stress responses.

Conclusions:

  • ATM and ATR orchestrate distinct cellular responses to DNA damage and replication stress.
  • Understanding the precise localization and activation of these kinases is key to their function.
  • This knowledge is crucial for comprehending genome instability and cancer development.
Keywords:
DNA damage SignallingHomologous recombinationPIKKsProtein kinasesRegulationReplication stress

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