Oncotarget

Research Papers:

c-Fos-dependent miR-22 targets MDC1 and regulates DNA repair in terminally differentiated cells

Jung-Hee Lee, Seon-Joo Park, Seok Won Kim, Gurusamy Hariharasudhan, Sung-Mi Jung, Semo Jun, Jeongsik Yong and Ho Jin You _

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Oncotarget. 2017; 8:48204-48221. https://doi.org/10.18632/oncotarget.18389

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Abstract

Jung-Hee Lee1,2,*, Seon-Joo Park1,3,*, Seok Won Kim4,*, Gurusamy Hariharasudhan1,2, Sung-Mi Jung1,5, Semo Jun1,5, Jeongsik Yong6 and Ho Jin You1,5

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

2Department of Cellular and Molecular Medicine, Chosun University School of Medicine, Seosuk-dong, Gwangju, Republic of Korea

3Department of Premedical Sciences, Chosun University School of Medicine, Seosuk-dong, Gwangju, Republic of Korea

4Department of Neurosurgery, Chosun University School of Medicine, Seosuk-dong, Gwangju, Republic of Korea

5Department of Pharmacology, Chosun University School of Medicine, Seosuk-dong, Gwangju, Republic of Korea

6Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota Twin Cities, Minneapolis, Minnesota, United States of America

*These authors have contributed equally to this work

Correspondence to:

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

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

Jeongsik Yong, email: jyong@umn.edu

Keywords: miR-22, MDC1, c-Fos, differentiation, DNA repair

Received: October 04, 2016     Accepted: May 01, 2017     Published: June 07, 2017

ABSTRACT

Terminally differentiated cells have a reduced capacity to repair double-stranded breaks (DSB) in DNA, however, the underlying molecular mechanism remains unclear. Here, we show that miR-22 is upregulated during postmitotic differentiation of human breast MCF-7 cells, hematopoietic HL60 and K562 cells. Increased expression of miR-22 in differentiated cells was associated with decreased expression of MDC1, a protein that plays a key role in the response to DSBs. This downregulation of MDC1 was accompanied by reduced DSB repair, impaired recruitment of the protein to the site of DNA damage following IR. Conversely, inhibiting miR-22 enhanced MDC1 protein levels, recovered MDC1 foci, fully rescued DSB repair in terminally differentiated cells. Moreover, MDC1 levels, IR-induced MDC1 foci, and the efficiency of DSB repair were fully rescued by siRNA-mediated knockdown of c-Fos in differentiated cells. These findings indicate that the c-Fos/miR-22/MDC1 axis plays a relevant role in DNA repair in terminally differentiated cells, which may facilitate our understanding of molecular mechanism underlying the downregulating DNA repair in differentiated cells.


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