c-Fos-dependent miR-22 targets MDC1 and regulates DNA repair in terminally differentiated cells
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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
Ho Jin You, email: email@example.com
Jung-Hee Lee, email: firstname.lastname@example.org
Jeongsik Yong, email: email@example.com
Keywords: miR-22, MDC1, c-Fos, differentiation, DNA repair
Received: October 04, 2016 Accepted: May 01, 2017 Published: June 07, 2017
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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