Activation of mammalian Chk1 during DNA replication arrest

  • Feijoo C
  • Hall-Jackson C
  • Wu R
  • et al.
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Abstract

Checkpoints maintain order and fidelity in the cell cycle by blocking late-occurring events when earlier events are improperly executed. Here we describe evidence for the participation of Chk1 in an intra-S phase checkpoint in mammalian cells. We show that both Chk1 and Chk2 are phosphorylated and activated in a caffeine-sensitive signaling pathway during S phase, but only in response to replication blocks, not during normal S phase progression. Replication block–induced activation of Chk1 and Chk2 occurs normally in ataxia telangiectasia (AT) cells, which are deficient in the S phase response to ionizing radiation (IR). Resumption of synthesis after removal of replication blocks correlates with the inactivation of Chk1 but not Chk2. Using a selective small molecule inhibitor, cells lacking Chk1 function show a progressive change in the global pattern of replication origin firing in the absence of any DNA replication. Thus, Chk1 is apparently necessary for an intra-S phase checkpoint, ensuring that activation of late replication origins is blocked and arrested replication fork integrity is maintained when DNA synthesis is inhibited.

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Feijoo, C., Hall-Jackson, C., Wu, R., Jenkins, D., Leitch, J., Gilbert, D. M., & Smythe, C. (2001). Activation of mammalian Chk1 during DNA replication arrest. The Journal of Cell Biology, 154(5), 913–924. https://doi.org/10.1083/jcb.200104099

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