Distinct modes of ATR activation after replication stress and DNA double-strand breaks in Caenorhabditis elegans.
ATM and ATR are key components of the DNA damage checkpoint. ATR primarily responds to UV damage and replication stress, yet may also function with ATM in the checkpoint response to DNA double-strand breaks (DSBs), although this is less clear. Here, we show that atl-1 (Caenorhabditis elegans ATR) and rad-5/clk-2 prevent mitotic catastrophe, function in the S-phase checkpoint and also cooperate with atm-1 in the checkpoint response to DSBs after ionizing radiation (IR) to induce cell cycle arrest or apoptosis via the cep-1(p53)/egl-1 pathway. ATL-1 is recruited to stalled replication forks by RPA-1 and functions upstream of rad-5/clk-2 in the S-phase checkpoint. In contrast, mre-11 and atm-1 are dispensable for ATL-1 recruitment to stalled replication forks. However, mre-11 is required for RPA-1 association and ATL-1 recruitment to DSBs. Thus, DNA processing controlled by mre-11 is important for ATL-1 activation at DSBs but not following replication fork stalling. We propose that atl-1 and rad-5/clk-2 respond to single-stranded DNA generated by replication stress and function with atm-1 following DSB resection.
Garcia-Muse
Tatiana
T
DNA Damage Response Laboratory, Cancer Research UK, The London Research Institute, Clare Hall Laboratories, South Mimms, UK.
Boulton
Simon J
SJ
D000818:Animals; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism / Q000502:physiology*; D002453:Cell Cycle; D002467:Cell Nucleus / Q000378:metabolism; D004249:DNA Damage; D004261:DNA Replication; D008540:Meiosis; D008856:Microscopy, Fluorescence; D008938:Mitosis; D008954:Models, Biological; D008957:Models, Genetic; D009154:Mutation; D010770:Phosphotransferases / Q000378:metabolism / Q000502:physiology*; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D011839:Radiation, Ionizing; D011995:Recombination, Genetic; D012097:Repressor Proteins / Q000378:metabolism; D016196:S Phase; D034501:Telomere-Binding Proteins / Q000378:metabolism; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays
C438244:CEP-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; C112486:EGL-1 protein, C elegans; D012097:Repressor Proteins; D034501:Telomere-Binding Proteins; D016159:Tumor Suppressor Protein p53; C438752:clk-2 protein, C elegans; C423224:mre-11 protein, C elegans; C576885:Atl-1 protein, C elegans; D010770:Phosphotransferases; D064007:Ataxia Telangiectasia Mutated Proteins