miR146a-mediated targeting of FANCM during inflammation compromises genome integrity

Devakumar Sundaravinayagam, Hye Rim Kim, Ting Ting Wu, Hyun Hee Kim, Hyun Seo Lee, Semo Jun, JeongHeon Cha, Younghoon Kee, Ho Jin You, Jung Hee Lee

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)45976-45994
Number of pages19
JournalOncotarget
Volume7
Issue number29
DOIs
Publication statusPublished - 2016 Jan 1

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Genome
Inflammation
DNA Damage
Phenotype
Fanconi Anemia
Recombinational DNA Repair
3' Untranslated Regions
Helicobacter Infections
MicroRNAs
Helicobacter pylori
DNA Repair
Cisplatin
Stomach
Carcinogenesis
Down-Regulation
Cell Line
Genes
Neoplasms

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Sundaravinayagam, D., Kim, H. R., Wu, T. T., Kim, H. H., Lee, H. S., Jun, S., ... Lee, J. H. (2016). miR146a-mediated targeting of FANCM during inflammation compromises genome integrity. Oncotarget, 7(29), 45976-45994. https://doi.org/10.18632/oncotarget.10275
Sundaravinayagam, Devakumar ; Kim, Hye Rim ; Wu, Ting Ting ; Kim, Hyun Hee ; Lee, Hyun Seo ; Jun, Semo ; Cha, JeongHeon ; Kee, Younghoon ; You, Ho Jin ; Lee, Jung Hee. / miR146a-mediated targeting of FANCM during inflammation compromises genome integrity. In: Oncotarget. 2016 ; Vol. 7, No. 29. pp. 45976-45994.
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Sundaravinayagam, D, Kim, HR, Wu, TT, Kim, HH, Lee, HS, Jun, S, Cha, J, Kee, Y, You, HJ & Lee, JH 2016, 'miR146a-mediated targeting of FANCM during inflammation compromises genome integrity', Oncotarget, vol. 7, no. 29, pp. 45976-45994. https://doi.org/10.18632/oncotarget.10275

miR146a-mediated targeting of FANCM during inflammation compromises genome integrity. / Sundaravinayagam, Devakumar; Kim, Hye Rim; Wu, Ting Ting; Kim, Hyun Hee; Lee, Hyun Seo; Jun, Semo; Cha, JeongHeon; Kee, Younghoon; You, Ho Jin; Lee, Jung Hee.

In: Oncotarget, Vol. 7, No. 29, 01.01.2016, p. 45976-45994.

Research output: Contribution to journalArticle

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Sundaravinayagam D, Kim HR, Wu TT, Kim HH, Lee HS, Jun S et al. miR146a-mediated targeting of FANCM during inflammation compromises genome integrity. Oncotarget. 2016 Jan 1;7(29):45976-45994. https://doi.org/10.18632/oncotarget.10275