Rad50 mediates DNA demethylation to establish pluripotent reprogramming

Abstract

Regenerative medicine: Protein boosts stem cell generation process Heightened expression of a DNA repair protein improves efficiency when generating induced pluripotent stem cells (iPSCs) for use in regenerative medicine. DNA demethylation - the removal of methyl groups from one of the DNA bases, cytosine - is required for effective reprogramming of cells other than sperm and egg cells to create iPSCs. Ineffective demethylation has been a key challenge for scientists to overcome in generating iPSCs efficiently. Now, Jongpil Kim and co-workers at Dongguk University in Seoul, South Korea, have demonstrated that the DNA repair protein Rad50 plays a regulatory role in DNA demethylation during cell reprogramming. Rad50 interacts with a key enzyme involved in demethylation, boosting the efficiency of the process. The team found that overexpressing Rad50 increased DNA demethylation during reprogramming, enhancing the efficiency of iPSC generation. Blocking Rad50 had the opposite effect. DNA demethylation is characterized by the loss of methyl groups from 5-methylcytosine, and this activity is involved in various biological processes in mammalian cell development and differentiation. In particular, dynamic DNA demethylation in the process of somatic cell reprogramming is required for successful iPSC generation. In the present study, we reported the role of Rad50 in the DNA demethylation process during somatic cell reprogramming. We found that Rad50 was highly expressed in pluripotent stem cells and that Rad50 regulated global DNA demethylation levels. Importantly, the overexpression of Rad50 resulted in the enhanced efficiency of iPSC generation via increased DNA demethylation, whereas Rad50 knockdown led to DNA hypermethylation, which suppressed somatic cell reprogramming into iPSCs. Moreover, we found that Rad50 associated with Tet1 to facilitate the DNA demethylation process in pluripotent reprogramming. Therefore, our findings highlight the novel role of Rad50 in the DNA demethylation process during somatic cell reprogramming.