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Exogenous 8-oxo-dG is not utilized for nucleotide synthesis but enhances the accumulation of 8-oxo-Gua in DNA through error-prone DNA synthesis
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Kim, Ja-Eun | - |
dc.contributor.author | Hyun, Jin-Won | - |
dc.contributor.author | Hayakawa, Hiroshi | - |
dc.contributor.author | Choi, Seongwon | - |
dc.contributor.author | Choi, Jinhee | - |
dc.contributor.author | Chung, Myung-Hee | - |
dc.date.accessioned | 2010-01-08 | - |
dc.date.available | 2010-01-08 | - |
dc.date.issued | 2006-02-14 | - |
dc.identifier.citation | Mutation Research 596 (2006) 128–136 | en |
dc.identifier.issn | 0027-5107 (Print) | - |
dc.identifier.uri | http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16472828 | - |
dc.identifier.uri | https://hdl.handle.net/10371/28580 | - |
dc.description.abstract | 7,8-Dihydro-8-oxoguanine (8-oxo-Gua) and its nucleoside in cytosol are derived from the repair of oxidative DNA and the cleanup of oxidatively damaged DNA precursors, respectively. While the harmful effects of 8-oxo-Gua present in DNA have been studied extensively, few have reported its effects on cytosolic function. Our previous study showed that the addition of 8-oxo-dG to culture media caused an accumulation of 8-oxo-Gua in nuclear DNA in several leukemic cells including KG-1, which lack 8-oxoguanine glycosylase 1 (OGG1) activity due to mutational loss. However, the mechanism underlying 8-oxo-Gua level increases in DNA has not been addressed. In this study, we elucidated the metabolic fate of 8-oxo-Gua-containing nucleotide and the effect of exogenous 8-oxo-dG on DNA synthesis in KG-1 cells. We found that 8-oxo-dGMP was rapidly dephosphorylated to 8-oxo-dG rather than phosphorylated to 8-oxo-dGDP, thus indicating that 8-oxo-Gua-containing molecule is not used as a substrate for DNA synthesis in KG-1 cells. In fact, radiolabeled 8-oxo-dG was incubated but radioactivity was not detected in nuclear DNA of KG-1 cells, showing that 8-oxo-dG is not directly incorporated into DNA. Interestingly, the activity of DNA polymerase beta, which synthesize DNA with low fidelity increased in KG-1 cells treated with 8-oxo-dG, whereas the expression of DNA polymerase alpha decreased. In addition, the accumulation of 8-oxo-Gua in KG-1 DNA was completely inhibited by a specific inhibitor of DNA polymerase beta. Thus, our findings address that the insertion of 8-oxo-dG into KG-1 DNA is not due to the direct incorporation of exogenous 8-oxo-dG, but rather to the inaccurate incorporation of endogenous 8-oxo-dGTP by DNA polymerase beta. It further suggests that 8-oxo-dG in the cytosol may function as an active molecule itself and perturb the well-defined DNA synthesis. | en |
dc.language.iso | en | - |
dc.publisher | Elsevier | en |
dc.subject | Base Sequence | en |
dc.subject | Cell Line, Tumor | en |
dc.subject | DNA Primers | en |
dc.subject | DNA Repair | en |
dc.subject | DNA Replication/*genetics | en |
dc.subject | Deoxyguanosine/*analogs & derivatives/pharmacokinetics | en |
dc.subject | Deoxyribonucleosides/biosynthesis | en |
dc.subject | Guanine/*analogs & derivatives/metabolism | en |
dc.subject | Humans | en |
dc.subject | Mutation | - |
dc.title | Exogenous 8-oxo-dG is not utilized for nucleotide synthesis but enhances the accumulation of 8-oxo-Gua in DNA through error-prone DNA synthesis | en |
dc.type | Article | en |
dc.contributor.AlternativeAuthor | 김자은 | - |
dc.contributor.AlternativeAuthor | 현진원 | - |
dc.contributor.AlternativeAuthor | 최성원 | - |
dc.contributor.AlternativeAuthor | 최진희 | - |
dc.contributor.AlternativeAuthor | 정명희 | - |
dc.identifier.doi | 10.1016/j.mrfmmm.2005.12.004 | - |
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