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

• Type of Material: Article
• Authors: Baocheng Hu, Emory University; Xiang Wang, Emory University; Shuofeng Hu, Beijing Institute of Basic Medical Sciences; Xiaomin Ying, Beijing Institute of Basic Medical Sciences; Ping Wang, Emory University; Xiangming Zhang, Emory University; Jian Wang, Emory University; Hongyan Wang, Emory University; Ya Wang, Emory University
• Language: English
• Date: 2017-02-24
• Publisher: American Society for Biochemistry and Molecular Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1074/jbc.M116.772392
• Title of Journal or Parent Work: Journal of Biological Chemistry
• ISSN: 0021-9258
• Volume: 292
• Issue: 8
• Start Page: 3531
• End Page: 3540
• Grant/Funding Information: This work was also supported by China National High Technology Research and Development Program Grant 2014AA020604 (to X. Y.).; The Winship Cancer Institute of Emory University was supported by National Institutes of Health Grant P30CA138292.; This work was supported by National Institutes of Health Grants CA186129 and CA185882 (to Y. W.) and P30CA138292 (to Winship Institute).
• Keywords: homologous recombination repair; HUMAN CANCERS; non-homologous end-joining; radiation biology; ionizing radiation; GSK3; threonine protein kinase (DNA-PK); miR-21; TUMOR-SUPPRESSOR GENE; DNA repair; cellular regulation; LUNG TUMORIGENESIS; microRNA (miRNA); PROTEIN-KINASE; PATHWAY; Life Sciences & Biomedicine; DAMAGE RESPONSE; MICRORNA-21; CELL-CYCLE; HOMOLOGOUS RECOMBINATION REPAIR; DNA double strand breaks; DNA-dependent serine; Science & Technology; CYCLIN D1; Biochemistry & Molecular Biology
• Research Categories: Biology, Molecular; Engineering, Biomedical; Chemistry, Biochemistry

Abstract

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.