Mapping structurally defined guanine oxidation products along DNA duplexes: influence of local sequence context and endogenous cytosine methylation.
Mapping structurally defined guanine oxidation products along DNA duplexes: influence of local sequence context and endogenous cytosine methylation.
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沿DNA双链体结构定义的鸟嘌呤氧化产物映射：局部序列上下文和内源性胞嘧啶甲基化的影响。
DOI：
10.1021/ja411636j
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发表时间：
2014-03-19
影响因子：
15
通讯作者：
Tretyakova N
中科院分区：
文献类型：
--
作者：
Ming X;Matter B;Song M;Veliath E;Shanley R;Jones R;Tretyakova N
活性氧对DNA的氧化是非随机的，可能导致核碱基损伤的积累和基因组内特定位点的突变。我们现在提出的第一个定量数据的序列依赖性形成的结构定义的氧化核碱基加合物沿沿着p53基因衍生的DNA双链体使用一种新的同位素标记为基础的方法。我们的研究结果表明，在双链DNA中，2，2，4-三氨基-2 H-oxal-5-酮（Z）和8-氧代-7，8-二氢-2 ′-脱氧鸟苷（OG）的产率与局部碱基序列的上下文有差异。虽然这两种损伤在内源性甲基化的MeCG二核苷酸内和几种鸟嘌呤的5′ G处过度产生，但在双链体末端的溶剂暴露的鸟嘌呤核碱基处强烈优选形成Z（但不是OG）。MeCG序列的靶向氧化可能是由于与MeC配对的鸟嘌呤碱基的电离势降低以及邻近MeC：G碱基对的核黄素光敏剂的优先嵌入引起的。重要的是，一些最频繁氧化的位置分别与密码子245（GGC）、248（CGG）和158（CGC）处的已知p53肺癌突变“热点”一致，支持DNA氧化降解在肺癌起始中的可能作用。
DNA oxidation by reactive oxygen species is nonrandom, potentially leading to accumulation of nucleobase damage and mutations at specific sites within the genome. We now present the first quantitative data for sequence-dependent formation of structurally defined oxidative nucleobase adducts along p53 gene-derived DNA duplexes using a novel isotope labeling-based approach. Our results reveal that local nucleobase sequence context differentially alters the yields of 2,2,4-triamino-2H-oxal-5-one (Z) and 8-oxo-7,8-dihydro-2′-deoxyguanosine (OG) in double stranded DNA. While both lesions are overproduced within endogenously methylated MeCG dinucleotides and at 5′ Gs in runs of several guanines, the formation of Z (but not OG) is strongly preferred at solvent-exposed guanine nucleobases at duplex ends. Targeted oxidation of MeCG sequences may be caused by a lowered ionization potential of guanine bases paired with MeC and the preferential intercalation of riboflavin photosensitizer adjacent to MeC:G base pairs. Importantly, some of the most frequently oxidized positions coincide with the known p53 lung cancer mutational “hotspots” at codons 245 (GGC), 248 (CGG), and 158 (CGC) respectively, supporting a possible role of oxidative degradation of DNA in the initiation of lung cancer.
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影响因子：
3.9
作者：
Greenberg, MM
通讯作者：
Greenberg, MM
影响因子：
4.7
作者：
HAUSHEER, FH;RAO, SN;BAYLIN, SB
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BAYLIN, SB
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3.3
作者：
Douki, T;Cadet, J
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作者：
Hirakawa, K;Suzuki, H;Kawanishi, S
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2.9
作者：
Chen, ZX;Riggs, AD
通讯作者：
Riggs, AD