HMGA2 protein could also have an effect on DNA-PKcs. HMGA2 delays the release of DNA-PKcs from sites of double-strand breaks, interfering with DNA repair by non-homologous end joining and causing chromosomal aberrations. The let-7a microRNA normally represses the HMGA2 gene. In normal adult tissues, almost no HMGA2 protein is present. In many cancers, let-7 microRNA is repressed. As an example, in breast cancers the promoter region controlling let-7a-3/let-7b microRNA is frequently repressed by hypermethylation. Epigenetic reduction or absence of let-7a microRNA allows high expression of the HMGA2 protein and this would lead to defective expression of DNA-PKcs.
