Oncotarget

Research Papers:

This article has been corrected. Correction in: Oncotarget. 2020; 11:2024-2025.

miR146a-mediated targeting of FANCM during inflammation compromises genome integrity

Devakumar Sundaravinayagam, Hye Rim Kim, TingTing Wu, Hyun Hee Kim, Hyun-Seo Lee, Semo Jun, Jeong-Heon Cha, Younghoon Kee, Ho Jin You and Jung-Hee Lee _

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Oncotarget. 2016; 7:45976-45994. https://doi.org/10.18632/oncotarget.10275

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Abstract

Devakumar Sundaravinayagam1,2,*, Hye Rim Kim1,3,*, TingTing Wu1,3,*, Hyun Hee Kim1,3, Hyun-Seo Lee1,2, Semo Jun1,2, Jeong-Heon Cha4, Younghoon Kee5, Ho Jin You1,2, Jung-Hee Lee1,3

1Laboratory of Genomic Instability and Cancer Therapeutics, Cancer Mutation Research Center, Chosun University School of Medicine, Gwangju, Republic of Korea

2Department of Pharmacology, Chosun University School of Medicine, Gwangju, Republic of Korea

3Department of Cellular and Molecular Medicine, Chosun University School of Medicine, Gwangju, Republic of Korea

4Department of Oral Biology, Department of Applied Life Science, The Graduate School, Yonsei University College of Dentistry, Seoul, Republic of Korea

5Department of Cell Biology, Microbiology, and Molecular Biology, College of Arts and Sciences, University of South Florida, Tampa, Florida, United States of America

*These authors contribute equally to this work

Correspondence to:

Jung-Hee Lee, email: jhlee75@chosun.ac.kr

Ho Jin You, email: hjyou@chosun.ac.kr

Younghoon Kee, email: ykee@usf.edu

Keywords: miR146a, FANCM, Fanconi anemia pathway, DNA interstrand cross-links (ICLs) repair, NF-κB

Received: March 03, 2016     Accepted: June 03, 2016     Published: June 24, 2016

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.


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