title: miR-21-mediated Radioresistance Occurs via Promoting Repair of DNA Double Strand Breaks.
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 targetingGSK3B(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 bothGSK3BandCDC25A(a known target of miR-21), which neutralizes the effects of targeting GSK3B-inducedCDC25Aincrease 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.
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine, Winship Cancer Institute of Emory University, Atlanta, Georgia 30322.
authors.forename: Baocheng
authors.initials: B
authors.lastname: Hu
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine, Winship Cancer Institute of Emory University, Atlanta, Georgia 30322.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.affiliation: Beijing Institute of Basic Medical Sciences, Beijing 100850, China.
authors.forename: Shuofeng
authors.initials: S
authors.lastname: Hu
authors.affiliation: Beijing Institute of Basic Medical Sciences, Beijing 100850, China.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Ying
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine, Winship Cancer Institute of Emory University, Atlanta, Georgia 30322.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine, Winship Cancer Institute of Emory University, Atlanta, Georgia 30322.
authors.forename: Xiangming
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine, Winship Cancer Institute of Emory University, Atlanta, Georgia 30322.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine, Winship Cancer Institute of Emory University, Atlanta, Georgia 30322.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine, Winship Cancer Institute of Emory University, Atlanta, Georgia 30322. Electronic address: ywang94@emory.edu.
authors.forename: Ya
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000818:Animals; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D059766:DNA End-Joining Repair / Q000528:radiation effects; D004260:DNA Repair / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000528:radiation effects; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics; D011836:Radiation Tolerance; D059767:Recombinational DNA Repair / Q000528:radiation effects
chemical_list: D000071679:Glycogen Synthase Kinase 3 beta; D035683:MicroRNAs; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse; C531950:MIRN21 microRNA, mouse
keywords: DNA double strand breaks; DNA repair; DNA-dependent serine/threonine protein kinase (DNA-PK); GSK3β; cellular regulation; homologous recombination repair; ionizing radiation; miR-21; microRNA (miRNA); non-homologous end-joining; radiation biology