MiR-21-mediated Radioresistance Is via Promoting Repair of DNA Double Strand Breaks [Gene Regulation]

MiR-21 as an oncogene that over-expresses in most human tumors involves radioresistance; however, the mechanism remains unclear. Here, we demonstrate that miR-21-mediated radioresistance is through promoting repair of DNA double strand breaks, which includes to facilitate both non-homologous end-joining (NHEJ) and homologous recombination repair (HRR). The miR-21-promoted NHEJ is through targeting GSK3B (a novel target of miR-21) that affects the CRY2/PP5 pathway and in turn increases DNA-PKcs activity. The miR-21-promoted HRR is through targeting both GSK3B and CDC25A (a known target of miR-21), which neutralizes the effects of targeting GSK3B-induced CDC25A increase since 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 GSK3 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.

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