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DNA damage response pathway in radioadaptive response
Masao S Sasaki1, Yosuke Ejima, Akira Tachibana
1Radiation Biology Center, Kyoto University, Yoshida-konoecho, Sakyo-ku, Kyoto, Japan. msasaki@emp.mbox.media.kyoto-u.ac.jp
Mutation Research
|July 11, 2002
Summary
Low-dose radiation triggers a radioadaptive response, enhancing cellular resistance to DNA damage. This defense mechanism relies on p53 protein and phosphatidylinositol 3-kinase (PI3K), working alongside apoptosis as a complementary system.
Area of Science:
- Radiobiology
- Molecular Biology
- Cellular Defense Mechanisms
Background:
- Radioadaptive response involves low-dose irradiation inducing resistance to subsequent higher doses.
- The molecular mechanisms underlying radioadaptive response are not fully understood.
- Previous work implicated protein kinase C (PKC), p38 mitogen-activated protein kinase (p38MAPK), and phospholipase C (PLC) in dose recognition and adaptive response.
Purpose of the Study:
- To elucidate the downstream effector pathways of X-ray-induced radioadaptive response.
- To investigate the role of specific genes (TP53, DNA-PKcs, ATM, FANCA) in the DNA damage response pathway during adaptive response.
- To explore the involvement of phosphatidylinositol 3-kinase (PI3K) in radioadaptive response.
Main Methods:
- Studied X-ray-induced adaptive response in cultured mouse and human cells with genetic deficiencies (TP53, DNA-PKcs, ATM, FANCA).
- Utilized wortmannin, a specific inhibitor of PI3K, to mimic priming irradiation.
- Administered p38MAPK inhibitors to assess their effect on adaptive response and apoptosis.
Main Results:
- p53 protein plays a key role in radioadaptive response; DNA-PKcs, ATM, and FANCA are not responsible.
- Wortmannin (PI3K inhibitor) mimicked priming irradiation, conferring resistance to subsequent X-ray-induced chromosome aberrations and apoptosis.
- Adaptive response, induced by low-dose X-rays or wortmannin, reduced apoptotic cell death.
- p38MAPK inhibition blocked adaptive response but did not suppress apoptosis.
Conclusions:
- Radioadaptive response and apoptosis act as a complementary defense system.
- p53 is crucial for directing radiation-induced DNA double-strand breaks (DSBs) towards adaptive repair pathways.
- A PKC-p38MAPK-PLC signaling circuit integrates damage signals into p53, modulating repair and apoptosis pathways.