OGG1-initiated base excision repair exacerbates oxidative stress-induced parthanatos

Abstract

Oxidative stress-induced DNA damage has been well acknowledged as a major cause leading to cell death, which is etiologically linked to ischemic injury and degenerative alterations. The most common oxidation product of DNA is base lesion 8-oxo-7,8-dihydroguanine (8-oxoG), which is repaired by 8-oxoG glycosylase1 (OGG1)-initiated baseexcision repair (BER) pathway (OGG1-BER); however, the role of OGG1-BER in oxidative stress-induced cell death is poorly investigated. DNA strand breaks and apurinic/apyrimidinic (AP) sites are effective substrates to activate DNA damage sensor poly(ADP-ribose) polymerase 1 (PARP1). Overactivation 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 result in hyperactivation of PARP1 and consequently cell death. To test, wild type, knockout, siRNA-depleted MEFs and neuroblastoma cells, or those expressing repair-deficient OGG1 mutants were oxidatively stressed and the role of OGG1 was examined. Results showed that OGG1-BER further increases the levels of ROS-induced DNA damage by generating repair intermediates, leading to PARP1 overactivation and cell death. Cells lacking or expressing repair-deficient OGG1 showed lower levels of DNA strand lesions, PARP1 activation, and nuclear translocation of apoptosis-inducing factor, resulting in the increased resistance to ROS-induced parthanatos. These results suggested that OGG1 guards genome integrity through either lesion repair or elimination of cells with malignant potential, to maintain the homeostasis of the host, which might depend on the magnitude of guanine oxidation.

In Vitro and In Vivo Efficacy of DNA Damage Repair Inhibitor Veliparib in Combination with Artesunate against Echinococcus granulosus

“…Therefore, inhibition of DNA repair would be the most effective for this process [19,20]. The oxidative stress-induced DNA damages were mainly repaired by base excision repair (BER) [21] that involved the base pair deletion and generation of 8-OHdG [22]. As an important component of the BER pathway, poly (ADP-ribose) polymerase (PARP) is a multifunctional protein involved in the activation of the BER downstream repairing protein recruiting the DNA polymerase and ligase.…”

Mitochondrial and Nuclear DNA Oxidative Damage in Physiological and Pathological Aging

“…The level of 8-oxo2dG in the human brain is 10-fold higher in mtDNA compared with nDNA in individuals up to the age 70 and 15-fold higher in individuals older than 70 years of age (Mecocci et al, 1993). The increased level of 8-oxo2dG both in nuclear and mitochondrial genomes correlates with a significant decrease in the activity of OGG1 (Wang et al, 2018). Similarly, the most common oxidized base in RNA is 8hydroxyguanosine (8-OHG), increased levels of which are observed during aging and in age-related diseases ( Jacob et al, 2013).…”

Mechanisms of MTH1 inhibition-induced DNA strand breaks: The slippery slope from the oxidized nucleotide pool to genotoxic damage

“…In pancreatic cancer, depletion of OGG1 protects tumor cells from beta-lapachone-induced DNA damage and PARP1 hyperactivation [111,112]. Another study similarly reports, following oxidative stress, OGG1-deficient or depleted MEFs and neuroblastoma cells sustain a lower extent of DNA strand lesions and are protected against a form of PARP1 hyperactivation-dependent cell death called parthanatos, relative to their OGG1-functional counterparts [113]. These findings further support that dysfunction in OGG1 (or other 8-oxodG processing mechanisms such as MUTYH) could antagonize the tumor-inhibitory effects of MTH1 inhibition by reducing its ability to produce genomic DNA breaks.…”