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Distinct modes of ATR activation after replication stress and DNA double-strand breaks in Caenorhabditis elegans

Tatiana Garcia-Muse1, Simon J Boulton

  • 1DNA Damage Response Laboratory, Cancer Research UK, The London Research Institute, Clare Hall Laboratories, South Mimms, UK.

The EMBO Journal
|December 2, 2005
PubMed

Insights

The DNA damage response involves ATM and ATR proteins. This study shows Caenorhabditis elegans ATR (atl-1) cooperates with ATM (atm-1) to manage DNA double-strand breaks and replication stress.

Area of Science:

  • Cellular Biology
  • Genetics
  • Molecular Biology

Background:

  • ATM and ATR are critical for DNA damage checkpoints.
  • ATR typically responds to UV damage and replication stress.
  • ATR's role with ATM in DNA double-strand break (DSB) response is less understood.

Purpose of the Study:

  • To investigate the roles of Caenorhabditis elegans ATR (atl-1) and ATM (atm-1) in DNA damage response.
  • To elucidate the mechanism of ATL-1 recruitment and activation at stalled replication forks and DSBs.
  • To understand the cooperation between ATL-1, RAD-5/CLK-2, and ATM-1 in cell cycle control.

Main Methods:

  • Utilized Caenorhabditis elegans as a model organism.
  • Investigated protein recruitment to DNA lesions using genetic and molecular approaches.
  • Analyzed cell cycle arrest and apoptosis pathways involving cep-1(p53)/egl-1.

Main Results:

  • ATL-1 and RAD-5/CLK-2 prevent mitotic catastrophe and function in the S-phase checkpoint.
  • ATL-1 cooperates with ATM-1 in the response to ionizing radiation-induced DSBs.
  • ATL-1 is recruited to stalled replication forks by RPA-1, functioning upstream of RAD-5/CLK-2.
  • MRE-11 is required for ATL-1 recruitment to DSBs but not stalled forks, indicating distinct activation mechanisms.

Conclusions:

  • ATL-1 and RAD-5/CLK-2 respond to single-stranded DNA from replication stress.
  • ATM-1 collaborates with ATL-1 and RAD-5/CLK-2 following DSB resection.
  • DNA processing by MRE-11 is crucial for ATL-1 activation at DSBs, but not at stalled replication forks.

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