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Excision of 8-oxoguanine from methylated CpG dinucleotides by human 8-oxoguanine DNA glycosylase |
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| Authors: | Rustem D. Kasymov Inga R. Grin Anton V. Endutkin Serge L. Smirnov Alexander A. Ishchenko Murat K. Saparbaev Dmitry O. Zharkov |
| Affiliation: | 1. SB RAS Institute of Chemical Biology and Fundamental Medicine, 8 Lavrentieva Ave., Novosibirsk 630090, Russia;2. Groupe “Réparation de l’ADN”, CNRS UMR8200, Université Paris-Sud, Institut de Cancérologie Gustave Roussy, Villejuif, France;3. Department of Chemistry, Western Washington University, Bellingham, WA 98225-9150, USA;4. Department of Molecular Biology, Faculty of Natural Sciences, Novosibirsk State University, 2 Pirogova St., Novosibirsk 630090, Russia |
| Abstract: | CpG dinucleotides are targets for epigenetic methylation, many of them bearing 5-methylcytosine (mCyt) in the human genome. Guanine in this context can be easily oxidized to 8-oxoguanine (oxoGua), which is repaired by 8-oxoguanine-DNA glycosylase (OGG1). We have studied how methylation affects the efficiency of oxoGua excision from damaged CpG dinucleotides. Methylation of the adjacent cytosine moderately decreased the oxoGua excision rate while methylation opposite oxoGua lowered the rate of product release. Cytosine methylation abolished stimulation of OGG1 by repair endonuclease APEX1. The OGG1 S326C polymorphic variant associated with lung cancer showed poorer base excision and lost sensitivity to the opposite-base methylation. The overall repair in the system reconstituted from purified proteins decreased for CpG with mCyt in the damaged strand. |
| Keywords: | DNA repair Epigenetic methylation 5-Methylcytosine 8-Oxoguanine OGG1 |
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