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.
Highlights
Differentiated cells are characterized by permanent withdrawal from the cell cycle and a lack of genome replication
These findings indicate that the c-Fos/miR-22/mediator of DNA damage checkpoint 1 (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
Because miR-22 has been described as a differentiation-responsive miRNA [5, 23, 24] and because we have previously reported that it targets MDC1 [17], an important mediator of the DNA damage response (DDR) [25,26,27], we were interested in the miR-22
Summary
Differentiated cells are characterized by permanent withdrawal from the cell cycle and a lack of genome replication. While resistance to various genotoxic stressors increases during cellular differentiation, DNA repair is progressively attenuated upon cellular differentiation, and terminally differentiated cells accumulate numerous chromosomal lesions [1, 2]. Only some aspects of the molecular mechanisms that cause attenuation of DNA repair in terminally differentiated cells have been elucidated, such as the transcriptional downregulation of www.impactjournals.com/oncotarget specific repair proteins [3] and impairment of functional DDR signaling [4,5,6]. DSBs activate the DDR by triggering the kinase activity of the ataxia telangiectasia mutated protein (ATM), thereby initiating a signaling cascade in which the adaptor protein mediator of DNA damage checkpoint 1 (MDC1) is recruited to DSB sites. A reduction or lack of MDC1 has been observed in breast and lung carcinoma cells in humans [11], an observation that has both clinical and mechanistic implications
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