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Activation of ATM and Chk2 kinases in relation to the amount of DNA strand breaks. | LitMetric

Activation of ATM and Chk2 kinases in relation to the amount of DNA strand breaks.

Oncogene

Department of Experimental Oncology, Istituto Nazionale Tumori, Via G Venezian 1, 20133 Milan, Italy.

Published: October 2004

AI Article Synopsis

  • DNA damage checkpoint responses vary based on the type and extent of DNA lesions, suggesting that different components in the signaling network may react differently.
  • Research found that small doses of gamma-radiation (0.25 Gy) cause single-strand breaks (SSBs) to activate the ATM kinase and phosphorylation of several substrates, but do not fully activate Chk2.
  • In contrast, a higher dose (1 Gy) causing more than 19 double-strand breaks (DSBs) is required for full Chk2 activation, indicating that Chk2 is sensitive to higher levels of damage while ATM can respond to lower levels without initiating Chk2-dependent checkpoints.

Article Abstract

The diverse checkpoint responses to DNA damage may reflect differential sensitivities by molecular components of the damage-signalling network to the type and amount of lesions. Here, we determined the kinetics of activation of the checkpoint kinases ATM and Chk2 (the latter substrate of ATM) in relation to the initial yield of genomic DNA single-strand (SSBs) and double-strand breaks (DSBs). We show that doses of gamma-radiation (IR) as low as 0.25 Gy, which generate vast numbers of SSBs but only a few DSBs per cell (<8), promptly activate ATM kinase and induce the phosphorylation of the ATM substrates p53-Ser15, Nbs1-Ser343 and Chk2-Thr68. The full activation of Chk2 kinase, however, is triggered by treatments inflicting >19 DSBs per cell (e.g. 1 Gy), which cause Chk2 autophosphorylation on Thr387, Chk2-dependent accumulation of p21waf1 and checkpoint arrest in the S phase. Our results indicate that, in contrast to ATM, Chk2 activity is triggered by a greater number of DSBs, implying that, below a certain threshold level of lesions (<19 DSBs), DNA repair can occur through ATM, without enforcing Chk2-dependent checkpoints.

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Source
http://dx.doi.org/10.1038/sj.onc.1207986DOI Listing

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