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| Subject Categories: Genome Stability & Dynamics |
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| The EMBO Journal
(2005) 24, 4345–4355, doi:10.1038/sj.emboj.7600896 Published online 1 December 2005 |
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| Distinct modes of ATR activation after replication stress and DNA double-strand breaks in Caenorhabditis elegans |
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| Tatiana Garcia-Muse and Simon J Boulton |
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DNA Damage Response Laboratory, Cancer Research UK, The London Research Institute, Clare Hall Laboratories, South Mimms, UK To whom correspondence should be addressed Simon J Boulton, DNA Damage Response Laboratory, Cancer Research UK, The London Research Institute, Clare Hall Laboratories, Blanche Lane, South Mimms, Herts EN6 3LD, UK. Tel.: +44 1707 625774; Fax: +44 2072 693801; E-mail: simon.boulton@cancer.org.uk Received 30 August 2005; Accepted 10 November 2005; Published online 1 December 2005. |
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| Abstract |
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| 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. |
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| Keywords: ATR, checkpoint, DSBs, replication stress |
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