期刊
PROCEEDINGS OF THE JAPAN ACADEMY SERIES B-PHYSICAL AND BIOLOGICAL SCIENCES
卷 90, 期 9, 页码 365-372出版社
JAPAN ACAD
DOI: 10.2183/pjab.90.365
关键词
DNA double-strand break repair; non-homologous end-joining; XRCC4; DNA-PKcs; ATM
资金
- Ministry of Education, Culture, Sport, Science and Technology of Japan [21689033, 24390290]
- Takeda Science Foundation
- Tokyo Biochemical Research Foundation
- Japan Society for the Promotion of Sciences
- Grants-in-Aid for Scientific Research [21689033, 24390290] Funding Source: KAKEN
XRCC4 (X-ray cross-complementation group 4) is a protein associated with DNA ligase IV, which is thought to join two DNA ends at the final step of DNA double-strand break repair through non-homologous end-joining. It has been shown that, in response to irradiation or treatment with DNA damaging agents, XRCC4 undergoes phosphorylation, requiring DNA-PK. Here we explored possible role of ATM, which is structurally related to DNA-PK, in the regulation of XRCC4. The radiosensitizing effects of DNA-PK inhibitor and/or ATM inhibitor were dependent on XRCC4. DNA-PK inhibitor and ATM inhibitor did not affect the ionizing radiation-induced chromatin recruitment of XRCC4. Ionizing radiation-induced phosphorylation of XRCC4 in the chromatin-bound fraction was largely inhibited by DNA-PK inhibitor but further diminished by the combination with ATM inhibitor. The present results indicated that XRCC4 phosphorylation is mediated through ATM as well as DNA-PK, although DNA-PK plays the major role. We would propose a possible model that DNA-PK and ATM acts in parallel upstream of XRCC4, regulating through phosphorylation.
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