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

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.

journal_name

Oncogene

journal_title

Oncogene

authors

Buscemi G,Perego P,Carenini N,Nakanishi M,Chessa L,Chen J,Khanna K,Delia D

doi

10.1038/sj.onc.1207986

subject

Has Abstract

pub_date

2004-10-07 00:00:00

pages

7691-700

issue

46

eissn

0950-9232

issn

1476-5594

pii

1207986

journal_volume

23

pub_type

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