Histone H2AX phosphorylation as a predictor of radiosensitivity and target for radiotherapy

被引:246
作者
Taneja, N
Davis, M
Choy, JS
Beckett, MA
Singh, R
Kron, SJ
Weichselbaum, RR
机构
[1] Univ Chicago, Ctr Mol Oncol, Chicago, IL 60637 USA
[2] Univ Chicago, Dept Radiat & Cellular Oncol, Chicago, IL 60637 USA
[3] Univ Chicago, Dept Mol Genet & Cell Biol, Chicago, IL 60637 USA
关键词
D O I
10.1074/jbc.M310030200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Based on the role of phosphorylation of the histone H2A variant H2AX in recruitment of DNA repair and checkpoint proteins to the sites of DNA damage, we have investigated gammaH2AX as a reporter of tumor radiosensitivity and a potential target to enhance the effectiveness of radiation therapy. Clinically relevant ionizing radiation (IR) doses induced similar patterns of gammaH2AX focus formation or immunoreactivity in radiosensitive and radioresistant human tumor cell lines and xenografted tumors. However, radiosensitive tumor cells and xenografts retained gammaH2AX for a greater duration than radioresistant cells and tumors. These results suggest that persistence of gammaH2AX after IR may predict tumor response to radiotherapy. We synthesized peptide mimics of the H2AX carboxyl-terminal tail to test whether antagonizing H2AX function affects tumor cell survival following IR. The peptides did not alter the viability of unirradiated tumor cells, but both blocked induction of gammaH2AX foci by IR and enhanced cell death in irradiated radioresistant tumor cells. These results suggest that H2AX is a potential molecular target to enhance the effects of radiotherapy.
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收藏
页码:2273 / 2280
页数:8
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