Poly(ADP-ribose) polymerase-1 inhibits ATM kinase activity in DNA damage response |
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Authors: | Watanabe Fumiaki Fukazawa Hidesuke Masutani Mitsuko Suzuki Hiroshi Teraoka Hirobumi Mizutani Shuki Uehara Yoshimasa |
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Affiliation: | Department of Bioactive Molecules, National Institute of Infectious Disease, 1-23-1 Toyama, Shinjyuku-ku, Tokyo 162-8640, Japan. |
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Abstract: | DNA double-strand breaks (DSB) mobilize DNA-repair machinery and cell cycle checkpoint by activating the ataxia-telangiectasia (A-T) mutated (ATM). Here we show that ATM kinase activity is inhibited by poly(ADP-ribose) polymerase-1 (PARP-1) in vitro. It was shown by biochemical fractionation procedure that PARP-1 as well as ATM increases at chromatin level after induction of DSB with neocarzinostatin (NCS). Phosphorylation of histone H2AX on serine 139 and p53 on serine 15 in Parp-1 knockout (Parp-1(-/-)) mouse embryonic fibroblasts (MEF) was significantly induced by NCS treatment compared with MEF derived from wild-type (Parp-1(+/+)) mouse. NCS-induced phosphorylation of histone H2AX on serine 139 in Parp-1(-/-) embryonic stem cell (ES) clones was also higher than that in Parp-1(+/+) ES clone. Furthermore, in vitro, PARP-1 inhibited phosphorylation of p53 on serine 15 and (32)P-incorporation into p53 by ATM in a DNA-dependent manner. These results suggest that PARP-1 negatively regulates ATM kinase activity in response to DSB. |
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Keywords: | ATM PARP-1 DNA double-strand breaks p53 and histone H2AX |
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