miR146a-mediated targeting of FANCM during inflammation compromises genome integrity

• DOI: 10.18632/oncotarget.10275
• Publication Date: 2016-06-24T20:07:00Z
• Authors: Devakumar Sundara...; Hye Rim Kim; TingTing Wu; Hyun Hee Kim; Hyun-Seo Lee; Semo Jun; Jeong-Heon Cha; Younghoon Kee; Ho Jin You; Jung-Hee Lee
• Keywords: 0301 basic medicine; Gene Expression Regulation/genetics*; 570; DNA Repair; 610; Cell Transformation; Microbiology; NF-κB; Cell Line; Cell and Developmental Biology; 03 medical and health sciences; DNA Repair/physiology; FANCM; Cell Line, Tumor; Inflammation/genetics; Humans; Fanconi anemia pathway; Molecular Biology; Inflammation; Tumor; DNA Damage/physiology; DNA Helicases/genetics; Inflammation/metabolism; DNA Helicases; Life Sciences; NF-κB; Cell Biology; Neoplastic/genetics; MicroRNAs/genetics*; 3. Good health; MicroRNAs; Cell Transformation, Neoplastic; Gene Expression Regulation; DNA interstrand cross-links (ICLs) repair; miR146a; DNA Helicases/biosynthesis*; Inflammation/pathology; Research Paper; DNA Damage

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.