title: miR146a-mediated targeting of FANCM during inflammation compromises genome integrity.
abstract: Inflammation is a potent inducer of tumorigenesis. Increased DNA damage or loss of genome integrity is thought to be one of the mechanisms linking inflammation and cancer development. It has been suggested that NF-κB-induced microRNA-146 (miR146a) may be a mediator of the inflammatory response. Based on our initial observation that miR146a overexpression strongly increases DNA damage, we investigated its potential role as a modulator of DNA repair. Here, we demonstrate that FANCM, a component in the Fanconi Anemia pathway, is a novel target of miR146a. miR146a suppressed FANCM expression by directly binding to the 3' untranslated region of the gene. miR146a-induced downregulation of FANCM was associated with inhibition of FANCD2 monoubiquitination, reduced DNA homologous recombination repair and checkpoint response, failed recovery from replication stress, and increased cellular sensitivity to cisplatin. These phenotypes were recapitulated when miR146a expression was induced by overexpressing the NF-κB subunit p65/RelA or Helicobacter pylori infection in a human gastric cell line; the phenotypes were effectively reversed with an anti-miR146a antagomir. These results suggest that undesired inflammation events caused by a pathogen or over-induction of miR146a can impair genome integrity via suppression of FANCM.
authors.affiliation: Laboratory of Genomic Instability and Cancer Therapeutics, Cancer Mutation Research Center, Chosun University School of Medicine, Gwangju, Republic of Korea.|Department of Pharmacology, Chosun University School of Medicine, Gwangju, Republic of Korea.
authors.forename: Devakumar
authors.initials: D
authors.lastname: Sundaravinayagam
authors.affiliation: Laboratory of Genomic Instability and Cancer Therapeutics, Cancer Mutation Research Center, Chosun University School of Medicine, Gwangju, Republic of Korea.|Department of Cellular and Molecular Medicine, Chosun University School of Medicine, Gwangju, Republic of Korea.
authors.forename: Hye Rim
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Laboratory of Genomic Instability and Cancer Therapeutics, Cancer Mutation Research Center, Chosun University School of Medicine, Gwangju, Republic of Korea.|Department of Cellular and Molecular Medicine, Chosun University School of Medicine, Gwangju, Republic of Korea.
authors.forename: TingTing
authors.initials: T
authors.lastname: Wu
authors.affiliation: Laboratory of Genomic Instability and Cancer Therapeutics, Cancer Mutation Research Center, Chosun University School of Medicine, Gwangju, Republic of Korea.|Department of Cellular and Molecular Medicine, Chosun University School of Medicine, Gwangju, Republic of Korea.
authors.forename: Hyun Hee
authors.initials: HH
authors.lastname: Kim
authors.affiliation: Laboratory of Genomic Instability and Cancer Therapeutics, Cancer Mutation Research Center, Chosun University School of Medicine, Gwangju, Republic of Korea.|Department of Pharmacology, Chosun University School of Medicine, Gwangju, Republic of Korea.
authors.forename: Hyun-Seo
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Laboratory of Genomic Instability and Cancer Therapeutics, Cancer Mutation Research Center, Chosun University School of Medicine, Gwangju, Republic of Korea.|Department of Pharmacology, Chosun University School of Medicine, Gwangju, Republic of Korea.
authors.forename: Semo
authors.initials: S
authors.lastname: Jun
authors.affiliation: Department of Oral Biology, Department of Applied Life Science, The Graduate School, Yonsei University College of Dentistry, Seoul, Republic of Korea.
authors.forename: Jeong-Heon
authors.initials: JH
authors.lastname: Cha
authors.affiliation: Department of Cell Biology, Microbiology, and Molecular Biology, College of Arts and Sciences, University of South Florida, Tampa, Florida, United States of America.
authors.forename: Younghoon
authors.initials: Y
authors.lastname: Kee
authors.affiliation: Laboratory of Genomic Instability and Cancer Therapeutics, Cancer Mutation Research Center, Chosun University School of Medicine, Gwangju, Republic of Korea.|Department of Pharmacology, Chosun University School of Medicine, Gwangju, Republic of Korea.
authors.forename: Ho Jin
authors.initials: HJ
authors.lastname: You
authors.affiliation: Laboratory of Genomic Instability and Cancer Therapeutics, Cancer Mutation Research Center, Chosun University School of Medicine, Gwangju, Republic of Korea.|Department of Cellular and Molecular Medicine, Chosun University School of Medicine, Gwangju, Republic of Korea.
authors.forename: Jung-Hee
authors.initials: JH
authors.lastname: Lee
mesh_terms: D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D004249:DNA Damage / Q000502:physiology; D004265:DNA Helicases / Q000096:biosynthesis* / Q000235:genetics; D004260:DNA Repair / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*
chemical_list: C542542:MIRN146 microRNA, human; D035683:MicroRNAs; C518295:FANCM protein, human; D004265:DNA Helicases
keywords: DNA interstrand cross-links (ICLs) repair; FANCM; NF-κB; miR146a; Fanconi anemia pathway