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miR146a-mediated targeting of FANCM during inflammation compromises genome integrity
Devakumar Sundaravinayagam1,2, Hye Rim Kim1,3, TingTing Wu1,3
1Laboratory of Genomic Instability and Cancer Therapeutics, Cancer Mutation Research Center, Chosun University School of Medicine, Gwangju, Republic of Korea.
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.
Insights
Inflammation can increase cancer risk by damaging DNA. This study shows microRNA-146a (miR146a) impairs DNA repair by targeting FANCM, potentially linking inflammation to genome instability.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Inflammation is a known driver of cancer development.
- MicroRNA-146a (miR146a) is implicated in inflammatory responses.
- Overexpression of miR146a has been linked to increased DNA damage.
Purpose of the Study:
- To investigate the role of miR146a in DNA repair.
- To identify novel targets of miR146a involved in genome integrity.
- To explore the link between inflammation, miR146a, and DNA repair pathways.
Main Methods:
- Demonstrated FANCM as a direct target of miR146a via 3' UTR binding.
- Assessed DNA repair capacity, including homologous recombination and checkpoint response.
- Utilized NF-κB activation and Helicobacter pylori infection models in gastric cells.
- Employed anti-miR146a antagomirs to reverse observed phenotypes.
Main Results:
- miR146a directly suppresses FANCM expression.
- Downregulation of FANCM inhibits FANCD2 monoubiquitination and homologous recombination repair.
- miR146a impairs recovery from replication stress and increases sensitivity to cisplatin.
- Phenotypes are mimicked by NF-κB activation or H. pylori infection and reversed by antagomirs.
Conclusions:
- FANCM is a novel target of miR146a, mediating its effects on DNA repair.
- Over-induction of miR146a, potentially during inflammation, compromises genome integrity.
- This mechanism highlights a pathway linking inflammation-induced DNA damage to cancer risk.
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