title: MiR-96 downregulates REV1 and RAD51 to promote cellular sensitivity to cisplatin and PARP inhibition.
abstract: Cell survival after DNA damage relies on DNA repair, the abrogation of which causes genomic instability. The DNA repair protein RAD51 and the trans-lesion synthesis DNA polymerase REV1 are required for resistance to DNA interstrand cross-linking agents such as cisplatin. In this study, we show that overexpression of miR-96 in human cancer cells reduces the levels of RAD51 and REV1 and impacts the cellular response to agents that cause DNA damage. MiR-96 directly targeted the coding region of RAD51 and the 3'-untranslated region of REV1. Overexpression of miR-96 decreased the efficiency of homologous recombination and enhanced sensitivity to the PARP inhibitor AZD2281 in vitro and to cisplatin both in vitro and in vivo. Taken together, our findings indicate that miR-96 regulates DNA repair and chemosensitivity by repressing RAD51 and REV1. As a therapeutic candidate, miR-96 may improve chemotherapeutic efficacy by increasing the sensitivity of cancer cells to DNA damage.
authors: Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.
authors: Yemin
authors: Y
authors: Wang
authors: Jen-Wei
authors: JW
authors: Huang
authors: Philamer
authors: P
authors: Calses
authors: Christopher J
authors: CJ
authors: Kemp
authors: Toshiyasu
authors: T
authors: Taniguchi
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D052160:Benzothiazoles / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology*; D004260:DNA Repair; D015536:Down-Regulation; D005260:Female; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D009713:Nucleotidyltransferases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051135:Rad51 Recombinase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays; D000099270:Y-Family DNA Polymerases
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D052160:Benzothiazoles; D002945:Cisplatin; D035683:MicroRNAs; D009687:Nuclear Proteins; D009713:Nucleotidyltransferases; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051135:Rad51 Recombinase; C539976:2-(6-(methylamino)pyridin-3-yl)-1,3-benzothiazol-6-ol; C541492:MIRN96 microRNA, human; C495153:RAD51 protein, human; C429004:REV1 protein, human; D000099270:Y-Family DNA Polymerases