Detection of a mouse OGG1 fragment during caspase‐dependent apoptosis: Oxidative DNA damage and apoptosis

Abstract

We investigated the expression of mouse 8-oxoguanine DNA glycosylase 1 (mOGG1) in mouse non-parenchymal hepatocytes (NCTC) during etoposide-or mitomycin C (MMC)-induced apoptosis. We observed mOGG1 fragmentation in apoptotic cells. The apoptosis accompanying the fragmentation of mOGG1 was caspase-dependent. The mOGG1 fragment existed in both the cytoplasm and nucleus of the etoposide-treated NCTC, indicating that the mOGG1 fragment could be transferred into the nucleus. In addition, 8-hydroxyguanine (8-OH-Gua, 7,8-dihydro-8-oxoguanine) accumulated in the DNA of NCTC treated with etoposide, suggesting that the mOGG1 fragment might not function as a normal repair enzyme in etoposide-treated NCTC. Although we have not clarified in detail the mechanism and the significance of the mOGG1 fragmentation, further study of the fragmentation of DNA repair enzymes might provide insights into the relationship between oxidative DNA damage and apoptosis. (Cancer Sci 2004; 95: 634-638) ells are damaged by a number of environmental stresses, such as ultraviolet radiation, X-rays, heat shock, and chemical agents. Some of the stresses generate reactive oxygen species (ROS), which are highly toxic to cell maintenance processes and survival. ROS are known to induce several types of oxidative DNA damage, including premutagenic lesions, such as thymine glycol, 1) 5-hydroxymethyluracil, 2) 2-hydroxyadenine, 3) and 8-hydroxyguanine (8-OH-Gua). 4)8-OH-Gua is thought to be responsible for carcinogenesis, because it induces GC to TA transversion-type point mutations in DNA in vitro. 5,6) Experiments in both cultured cells and animals have supported this premise.7-11) Therefore, analyses of oxidative DNA damage should be useful to understand in detail the mechanisms of carcinogenesis. Moreover, the genes for the human and mouse glycosylase-type repair enzymes for 8-OHGua (hOGG1 and mOGG1) have been cloned. [12][13][14] The corresponding proteins have also been analyzed to study the mechanisms of carcinogenesis and to assess the cancer risks of chemical substances or environmental factors. [7][8][9][10][11] Several recent reports have suggested a relationship between oxidative DNA damage and the apoptotic process, [15][16][17] although, to our knowledge, only a few studies have investigated the relationship between 8-OH-Gua and apoptosis. Apoptosis is a physiological process of programmed cell death, which is characterized by distinct morphological changes and internucleosomal DNA fragmentation. The DNA damage induced by various stresses, including ROS, activates p53, which is an important molecule for the induction of cell cycle arrest or apoptosis in order to prevent oncogenesis. [18][19][20][21] The anticancer activities of some cancer chemotherapeutic agents, such as etoposide, mitomycin C (MMC), and cisplatin, are due to the induction of apoptosis. [22][23][24] Among these agents, etoposide has a topoisomerase II inhibitory action that is responsible for inducing apoptosis, and it recently was shown to be a pro-oxidant. 24) In our p...

Fragmentation of the DNA Repair Enzyme, OGG1, in Mouse Nonparenchymal Liver Cells by Arsenic Compounds

“…In the present study, the fragmentation of mOGG1 was detected in NCTC treated with arsenic compounds. Similar results were obtained in our previous studies, in which we detected the fragmentation of mOGG1 in carcinogentreated mouse liver or during caspase-dependent apoptosis in cultured mouse nonparenchymal hepatocytes (19,25). In those cases and the present study, the 8-OH-Gua accumulation was increased, suggesting that the fragmentation of OGG1 resulted in the increased level of 8-OH-Gua accumulation.…”

Topoisomerase II and tubulin inhibitors both induce the formation of apoptotic topoisomerase I cleavage complexes

“…In addition, caspases are also involved in the generation of ROS (32,33). In fact, z-VAD-fmk prevented VP-16-induced oxidative DNA lesions (23). Activation of caspases could therefore serve to generate the ROS that lead to apoptotic Top1cc.…”

“…Because Top1cc can be induced by ROS (22) and oxidative DNA lesions (4, 8 -10) and because VP-16 and doxorubicin generate ROS and oxidative DNA lesions (23,24), we tested whether the apoptotic Top1cc induced by Top2 inhibitors resulted from oxidative lesions. Quenching ROS with the antioxidant N-acetyl-L-cysteine prevented VP-16-induced Top1cc and apoptosis (Fig.…”

The dark side of a tumor suppressor: anti-apoptotic p53

“…In addition, OGG1 appears to be cleaved by caspases during drug-induced apoptosis. 55 Whether OGG1 cleavage merely occurs to remove an antiapoptotic protein or whether it amplifies the death response by creating a pro-apoptotic fragment as it was reported for the cleavage of the MMR protein MLH1 (see mismatch repair section) is presently unknown.…”