Abstract
The phosphatidyl inositol 3-kinase-like kinases (PIKKs), ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) regulate parallel damage response signalling pathways. ATM is reported to be activated by DNA double-strand breaks (DSBs), whereas ATR is recruited to single-stranded regions of DNA. Although the two pathways were considered to function independently, recent studies have demonstrated that ATM functions upstream of ATR following exposure to ionising radiation (IR) in S/G2. Here, we show that ATM phosphorylation at Ser1981, a characterised autophosphorylation site, is ATR-dependent and ATM-independent following replication fork stalling or UV treatment. In contrast to IR-induced ATM-S1981 phosphorylation, UV-induced ATM-S1981 phosphorylation does not require the Nbs1 C-terminus or Mre11. ATR-dependent phosphorylation of ATM activates ATM phosphorylation of Chk2, which has an overlapping function with Chk1 in regulating G2/M checkpoint arrest. Our findings provide insight into the interplay between the PIKK damage response pathways.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins / metabolism*
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Checkpoint Kinase 1
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Checkpoint Kinase 2
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DNA Replication* / drug effects
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DNA Replication* / radiation effects
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DNA-Binding Proteins / metabolism*
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Enzyme Activation / drug effects
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Enzyme Activation / radiation effects
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / pathology
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Fibroblasts / radiation effects
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G2 Phase / drug effects
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G2 Phase / radiation effects
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Histones / deficiency
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Humans
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Hydroxyurea / pharmacology
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Mice
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Mitosis / drug effects
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Mitosis / radiation effects
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Models, Biological
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Nuclear Proteins / metabolism
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Phosphoproteins / deficiency
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Phosphorylation / drug effects
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Phosphorylation / radiation effects
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Phosphoserine / metabolism
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Protein Kinases / metabolism
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Protein Serine-Threonine Kinases / deficiency
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Protein Serine-Threonine Kinases / metabolism*
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Protein Structure, Tertiary
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Tumor Suppressor Proteins / metabolism*
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Ultraviolet Rays*
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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H2AX protein, mouse
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Histones
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NBN protein, human
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Nuclear Proteins
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Phosphoproteins
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Tumor Suppressor Proteins
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Phosphoserine
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Protein Kinases
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Checkpoint Kinase 2
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ATM protein, human
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ATR protein, human
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Ataxia Telangiectasia Mutated Proteins
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Atm protein, mouse
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CHEK1 protein, human
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CHEK2 protein, human
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Checkpoint Kinase 1
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Chek1 protein, mouse
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Chek2 protein, mouse
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Protein Serine-Threonine Kinases
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Hydroxyurea