miR-21-mediated Radioresistance Occurs via Promoting Repair of DNA Double Strand Breaks

miR-21, as an oncogene that overexpresses in most human tumors, is involved in radioresistance; however, the mechanism remains unclear. Here, we demonstrate that miR-21-mediated radioresistance occurs through promoting repair of DNA double strand breaks, which includes facilitating both non-homologo...

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Bibliographic Details
Published in:The Journal of biological chemistry 2017-02, Vol.292 (8), p.3531-3540
Main Authors: Hu, Baocheng, Wang, Xiang, Hu, Shuofeng, Ying, Xiaomin, Wang, Ping, Zhang, Xiangming, Wang, Jian, Wang, Hongyan, Wang, Ya
Format: Article
Language:English
Subjects:
Animals
Cell Biology
Cell Line
cellular regulation
DNA Breaks, Double-Stranded - radiation effects
DNA double strand breaks
DNA End-Joining Repair - radiation effects
DNA repair
DNA Repair - radiation effects
DNA-dependent serine/threonine protein kinase (DNA-PK)
Gene Expression Regulation - radiation effects
Glycogen Synthase Kinase 3 beta - genetics
GSK3β
homologous recombination repair
Humans
ionizing radiation
Mice
Mice, Inbred C57BL
microRNA (miRNA)
MicroRNAs - genetics
miR-21
Neoplasms - genetics
non-homologous end-joining
radiation biology
Radiation Tolerance
Recombinational DNA Repair - radiation effects
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Summary:miR-21, as an oncogene that overexpresses in most human tumors, is involved in radioresistance; however, the mechanism remains unclear. Here, we demonstrate that miR-21-mediated radioresistance occurs through promoting repair of DNA double strand breaks, which includes facilitating both non-homologous end-joining (NHEJ) and homologous recombination repair (HRR). The miR-21-promoted NHEJ occurs through targeting GSK3B (a novel target of miR-21), which affects the CRY2/PP5 pathway and in turn increases DNA-PKcs activity. The miR-21-promoted HRR occurs through targeting both GSK3B and CDC25A (a known target of miR-21), which neutralizes the effects of targeting GSK3B-induced CDC25A increase because GSK3B promotes degradation of both CDC25A and cyclin D1, but CDC25A and cyclin D1 have an opposite effect on HRR. A negative correlation of expression levels between miR-21 and GSK3β exists in a subset of human tumors. Our results not only elucidate miR-21-mediated radioresistance, but also provide potential new targets for improving radiotherapy.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M116.772392