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

Buscemi, Giacomo, Perego, Paola, Carenini, Nives, Nakanishi, Makoto, Chessa, Luciana, Chen, Junjie, Khanna, Kum Kum and Delia, Domenico (2004) Activation of ATM and Chk2 kinases in relation to the amount of DNA strand breaks. Oncogene, 23 46: 7691-7700.


Author Buscemi, Giacomo
Perego, Paola
Carenini, Nives
Nakanishi, Makoto
Chessa, Luciana
Chen, Junjie
Khanna, Kum Kum
Delia, Domenico
Title Activation of ATM and Chk2 kinases in relation to the amount of DNA strand breaks
Journal name Oncogene   Check publisher's open access policy
ISSN 0950-9232
Publication date 2004
Sub-type Article (original research)
DOI 10.1038/sj.onc.1207986
Volume 23
Issue 46
Start page 7691
End page 7700
Total pages 10
Place of publication London, U.K.
Publisher Nature Publishing Group
Language eng
Subject 06 Biological Sciences
0601 Biochemistry and Cell Biology
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 -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.
Keyword Atm
Chk2
Dna Double Strand Breaks
Checkpoints
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Medicine Publications
 
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