Premium
Ku70/80 modulates ATM and ATR signaling pathways in response to DNA double strand breaks
Author(s) -
Kurimasa Akihiro,
Tomimatsu Nozomi,
Tahimic Candice GT,
Otsuki Akihiro,
Fukuhara Akiko,
Burma Sandeep,
Chen David J
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.lb34-a
Subject(s) - ku70 , phosphorylation , dna damage , kinase , non homologous end joining , ku80 , microbiology and biotechnology , dna pkcs , homologous recombination , dna repair , chemistry , bystander effect , dna , biology , dna binding protein , protein kinase a , biochemistry , immunology , gene , transcription factor
Double strand break (DSB) recognition is the first step in the DSB damage response and involves activation of ATM and phosphorylation of targets such as p53. It was reported that activation of ATR kinase by DSBs also occurs in an ATM‐dependent manner. On the other hand, Ku70/80 is known to participate at a later time point in the DSB response, recruiting DNA‐PKcs to facilitate non‐homologous end joining. Because Ku70/80 has a high affinity for broken DNA ends and is abundant in nuclei, we examined their possible involvement in other aspects of the DSB damage response, particularly in modulating the activity of ATM and other phosphatidylinositol (PI) 3‐related kinases during DSB recognition. We thus analyzed p53Ser18 phosphorylation in irradiated Ku‐deficient cells and observed persistent phosphorylation in these cells relative to wild type cells. ATM or ATR inhibition revealed that this phosphorylation is mainly mediated by ATM‐dependent ATR activity at 2h post‐ionizing radiation in wild type cells, whereas in Ku‐deficient cells, this occurs mainly through direct ATM activity, with a secondary contribution from ATR via a novel ATM‐independent mechanism. Using ATM/Ku70 double‐null cell lines, which we generated, we confirmed that ATM‐independent ATR activity contributed to persistent phosphorylation of p53Ser18 in Ku‐deficient cells at 12h post‐ionizing radiation. In summary, we discovered a novel role for Ku70/80 in modulating ATM‐dependent ATR activation during DSB damage response and demonstrated that these proteins confer a protective effect against ATM‐independent ATR activation at later stages of the DSB damage response.