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 p21(waf1) 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.
|Titolo:||Activation of ATM and Chk2 kinases in relation to the amount of DNA strand breaks|
BUSCEMI, GIACOMO (Primo)
|Parole Chiave:||ATM; Checkpoints; Chk2; DNA double-strand breaks|
|Settore Scientifico Disciplinare:||Settore BIO/11 - Biologia Molecolare|
|Data di pubblicazione:||2004|
|Digital Object Identifier (DOI):||10.1038/sj.onc.1207986|
|Appare nelle tipologie:||01 - Articolo su periodico|