OGG1-initiated Base Excision Repair Exacerbates Oxidative Stress-induced Parthanatos

Oxidative stress is a result of imbalance between the generation of reactive oxygen species?ROS?and the antioxidant defence systems.Oxidative stress-induced DNA damage has been well acknowledged as a major cause leading to cell death,which is etiologically linked to diabetes,ischemic injury,stroke,cardiovascular disease,Parkinson disease and degenerative alterations.The most common oxidation product of DNA is base lesion8-oxoguanine?8-oxoG?,which is repaired by 8-oxoG glycosylase1?OGG1?-initiated base excision repair?BER?pathway?OGG1-BER?;however,the role of OGG1-BER in oxidative stress-induced cell death is poorly investigated.Repair of apurinic/apyrimidinic?AP?sites and single-strand interruption with nonligatable termini are the common steps in the OGG1-BER pathway.DNA strand breaks and apurinic/apyrimidinic?AP?sites are effective substrates to activate DNA damage sensor poly?ADP-ribose?polymerase 1?PARP1?.Over-activation of PARP1 is associated with apoptosis inducing factor?AIF?-mediated and caspase-independent cell death?parthanatos?.We hypothesized that after an excessive oxidative insult,OGG1-BER generated strand breaks results in hyperactivation of PARP1,and consequently cell death.In this study,we used H2O2 to mimic oxidative stress.Firstly,it was clarified that oxidative stress-induced cell death is parthanatos one.Secondly,to test the role of OGG1 in parthanatos,wild type(Ogg1^+/+),knockout(Ogg1^-/-),siRNA-depleted and over expressive OGG1 MEFs were oxidatively stressed and the role of OGG1 was examined.The results showed that OGG1 excerbates H2O2-induced PARP1-dependent AIF-induced cell death.Furthermore,we used those expressing repair-deficient OGG1 combined with immunfluorscence,TUNEL and flow cytometry to explored the OGG1-BER pathway promoted parthanatos or not.Results show that OGG1-BER further increases levels of ROS-induced DNA damage by generating repair intermediates,PARP1 over-activation and nuclear translocation of AIF,and parthanatos.In the end,to explore the physiological and pathological significance of the above conclusions,SH-SY5Y neuroblastoma cells were utilized.Our data revealed that NMDA exposure increases the level of intracellular ROS and8-oxoG,moreover,OGG1 is implicated in NMDA-induced neuronal cell parthanatos.Taken together,this study found that OGG1-BER further increases levels of ROS-induced DNA damage by generating repair intermediates,PARP1 overactivation and nuclear translocation of AIF and parthanatos.This study preliminarily suggested link between DNA damage repair and cell death.The present study suggested that OGG1 guard genome integrity not only depending on its capability to repair the base lesions,but also through promoting cell death to eliminate the cells with malignant potentials,thus maintain the homeostasis and protect the host.