Defective DNA repair and increased chromatin binding of DNA repair factors in Down syndrome fibroblasts

摘要: Down syndrome (DS) is characterized by genetic instability, neurodegeneration, and premature aging. However, the molecular mechanisms leading to this phenotype are not yet well understood. Here, we report that DS fibroblasts from both fetal adult donors show presence of oxidative DNA base damage, such as dihydro-8-oxoguanine (8-oxodG), activation a damage response (DDR), already during unperturbed growth conditions. DDR with checkpoint was indicated histone H2AX Chk2 protein phosphorylation, increased p53 levels. In addition, were more sensitive induced potassium bromate, defective in removal 8-oxodG, compared age-matched cells control healthy donors. The analysis core proteins participating excision repair (BER), XRCC1 polymerase β, showed higher amounts these factors bound chromatin than cells, even absence damage. These findings occurred concomitance levels phosphorylated detected cells. results indicate exhibit BER deficiency, which associated prolonged association factors.