Lee Jung-Hee, Park Seon-Joo, Kim Seok Won, Hariharasudhan Gurusamy, Jung Sung-Mi, Jun Semo, Yong Jeongsik, Jin You Ho
Laboratory of Genomic Instability and Cancer Therapeutics, Cancer Mutation Research Center, Chosun University School of Medicine, Seosuk-dong, Gwangju, Republic of Korea.
Department of Cellular and Molecular Medicine, Chosun University School of Medicine, Seosuk-dong, Gwangju, Republic of Korea.
Oncotarget. 2017 Jul 18;8(29):48204-48221. doi: 10.18632/oncotarget.18389.
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.
终末分化细胞修复DNA双链断裂（DSB）的能力降低，然而，其潜在的分子机制仍不清楚。在此，我们表明miR-22在人乳腺癌MCF-7细胞、造血HL60和K562细胞的有丝分裂后分化过程中上调。分化细胞中miR-22表达的增加与MDC1表达的降低相关，MDC1是一种在对DSB的反应中起关键作用的蛋白质。MDC1的这种下调伴随着DSB修复的减少，以及在IR后该蛋白质募集到DNA损伤位点的受损。相反，抑制miR-22可提高MDC1蛋白水平，恢复MDC1病灶，完全挽救终末分化细胞中的DSB修复。此外，通过在分化细胞中用siRNA介导敲低c-Fos，MDC1水平、IR诱导的MDC1病灶以及DSB修复效率均得到完全挽救。这些发现表明，c-Fos/miR-22/MDC1轴在终末分化细胞的DNA修复中起相关作用，这可能有助于我们理解分化细胞中DNA修复下调的分子机制。
