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Oxidation of 8-Oxo-7,8-dihydro-2'-deoxyguanosine Leads to Substantial DNA-Histone Cross-Links within Nucleosome Core Particles.
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2018-11-19 , DOI: 10.1021/acs.chemrestox.8b00244 Jing Bai 1 , Yingqian Zhang 1 , Zhen Xi 1 , Marc M Greenberg 2 , Chuanzheng Zhou 1, 3
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2018-11-19 , DOI: 10.1021/acs.chemrestox.8b00244 Jing Bai 1 , Yingqian Zhang 1 , Zhen Xi 1 , Marc M Greenberg 2 , Chuanzheng Zhou 1, 3
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8-Oxo-7,8-dihydro-2'-deoxyguanosine(8-oxodGuo) is a common primary product of cellular oxidative DNA damage. 8-OxodGuo is more readily oxidized than 2'-deoxyguanosine (dG); a two-electron oxidation generates a highly reactive intermediate (OGox), which forms covalent adducts with nucleophiles, including OH-, free amines, and the side chains of amino acids such as lysine. We determined here that K3Fe(CN)6 oxidation of 8-oxodGuo in nucleosome core particles (NCPs) produces high yields, quantitative (i.e., 100%) in some cases, of DNA-protein cross-links (DPCs). The efficiency of DPC formation was closely related to 8-oxodGuo base pairing and location within the NCP and was only slightly decreased by adding the DNA-protective polyamine spermine to the system. Using NCPs that contained histone mutants, we determined that DPCs result predominantly from OGox trapping by the N-terminal histone amine. The DPCs were stable under physiological conditions and therefore could have important biological consequences. For instance, the essentially quantitative yield of DPCs at some positions within NCPs would reduce the yield of the mutagenic DNA lesions spiroiminodihydantoin and guanidinohydantoin produced from the common intermediate OGox, which in turn would affect mutation signatures of oxidative stress in a position-dependent manner. In summary, our findings indicate that site-specific incorporation of 8-oxodGuo into NCPs, followed by its oxidation, leads to DPCs with an efficiency depending on 8-oxodGuo location and orientation. Given that 8-oxodGuo formation is widespread in genomic DNA and that DPC formation is highly efficient, DPCs may occur in eukaryotic cells and may affect several important biological processes.
中文翻译：
8-Oxo-7,8-dihydro-2'-deoxyguanosine的氧化导致核小体核心颗粒中大量的DNA-组蛋白交联。
8-Oxo-7,8-dihydro-2'-deoxyguanosine（8-oxodGuo）是细胞氧化DNA损伤的常见主要产物。8-OxodGuo比2'-脱氧鸟苷（dG）更容易被氧化；两电子氧化生成高反应性中间体（OGox），该中间体与亲核试剂（包括OH-，游离胺和氨基酸的侧链，如赖氨酸）形成共价加合物。我们在这里确定，核小体核心颗粒（NCPs）中8-oxodGuo的K3Fe（CN）6氧化产生高产量，在某些情况下定量（例如100％）的DNA-蛋白质交联（DPC）。DPC形成的效率与NCP中的8-oxodGuo碱基配对和位置密切相关，并且通过向系统中添加DNA保护性多胺精胺而仅略有降低。使用包含组蛋白突变体的NCP，我们确定DPC主要是由N端组蛋白胺的OGox捕获引起的。DPC在生理条件下稳定，因此可能产生重要的生物学后果。例如，在NCP内某些位置上DPC的基本定量产量将降低由共同的中间OGox产生的致突变性DNA损伤螺线虫二乙内酰脲和胍基乙内酰脲的产率，这反过来将以位置依赖的方式影响氧化应激的突变特征。总而言之，我们的发现表明，将8-oxodGuo特异性结合到NCP中，然后进行氧化，导致DPC的效率取决于8-oxodGuo的位置和方向。鉴于8-oxodGuo的形成在基因组DNA中很普遍，而DPC的形成非常高效，
更新日期：2018-11-09
中文翻译：
8-Oxo-7,8-dihydro-2'-deoxyguanosine的氧化导致核小体核心颗粒中大量的DNA-组蛋白交联。
8-Oxo-7,8-dihydro-2'-deoxyguanosine（8-oxodGuo）是细胞氧化DNA损伤的常见主要产物。8-OxodGuo比2'-脱氧鸟苷（dG）更容易被氧化；两电子氧化生成高反应性中间体（OGox），该中间体与亲核试剂（包括OH-，游离胺和氨基酸的侧链，如赖氨酸）形成共价加合物。我们在这里确定，核小体核心颗粒（NCPs）中8-oxodGuo的K3Fe（CN）6氧化产生高产量，在某些情况下定量（例如100％）的DNA-蛋白质交联（DPC）。DPC形成的效率与NCP中的8-oxodGuo碱基配对和位置密切相关，并且通过向系统中添加DNA保护性多胺精胺而仅略有降低。使用包含组蛋白突变体的NCP，我们确定DPC主要是由N端组蛋白胺的OGox捕获引起的。DPC在生理条件下稳定，因此可能产生重要的生物学后果。例如，在NCP内某些位置上DPC的基本定量产量将降低由共同的中间OGox产生的致突变性DNA损伤螺线虫二乙内酰脲和胍基乙内酰脲的产率，这反过来将以位置依赖的方式影响氧化应激的突变特征。总而言之，我们的发现表明，将8-oxodGuo特异性结合到NCP中，然后进行氧化，导致DPC的效率取决于8-oxodGuo的位置和方向。鉴于8-oxodGuo的形成在基因组DNA中很普遍，而DPC的形成非常高效，
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