具有五个重复的人类端粒G-四联体通过环出DNA损伤来容纳8-Oxo-7,8-dihydroguanine,ACS Chemical Biology

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具有五个重复的人类端粒G-四联体通过环出DNA损伤来容纳8-Oxo-7,8-dihydroguanine
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2015-12-29 00:00:00 , DOI: 10.1021/acschembio.5b00844
Na An ₁ , Aaron M. Fleming ₁ , Cynthia J. Burrows ₁

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炎症和氧化应激产生的自由基将DNA中的鸟嘌呤（G）氧化为8-oxo-7,8-dihydroguanine（OG），并且该反应在富含G的端粒序列中很明显。在端粒中，OG不能通过修复途径有效去除，从而使其浓度得以增强，令人惊讶地对稳定性没有任何直接的负面影响。在本文中，OG是在人类端粒序列（TTAGGG）_n的五个重复序列中合成的，位于5个最前，最中间和3个最上端G轨道的5'-G处，代表了氧化的热点。将这些合成的低聚物折叠成适当的K ⁺ / Na ⁺量，以采用杂合的G-四链体折叠。OG的结构影响通过圆二色性，热熔融¹1 H NMR和α-溶血素纳米孔的单分子谱分析。根据这些结果，通过将损坏的G轨道循环以允许其他四个轨道采用混合G四联体，OG可以很好地适应五重复序列。这些结果与以前对OG在四重复端粒序列中的研究相悖，后者发现OG高度不稳定并引起折叠的显着重新定向。当更广泛地观察人端粒序列并考虑其他重复序列时，我们发现OG对结构的影响最小。该重复序列的可塑性解决了端粒中OG浓度如何增加而不会立即导致端粒不稳定或磨损的问题。

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Human Telomere G-Quadruplexes with Five Repeats Accommodate 8-Oxo-7,8-dihydroguanine by Looping out the DNA Damage

Inflammation and oxidative stress generate free radicals that oxidize guanine (G) in DNA to 8-oxo-7,8-dihydroguanine (OG), and this reaction is prominent in the G-rich telomere sequence. In telomeres, OG is not efficiently removed by repair pathways allowing its concentration to build, surprisingly without any immediate negative consequences to stability. Herein, OG was synthesized in five repeats of the human telomere sequence (TTAGGG)_n, at the 5′-G of the 5′-most, middle, and 3′-most G tracks, representing hotspots for oxidation. These synthetic oligomers were folded in relevant amounts of K⁺/Na⁺ to adopt hybrid G-quadruplex folds. The structural impact of OG was assayed by circular dichroism, thermal melting, ¹H NMR, and single-molecule profiling by the α-hemolysin nanopore. On the basis of these results, OG was well accommodated in the five-repeat sequences by looping out the damaged G track to allow the other four tracks to adopt a hybrid G-quadruplex. These results run counter to previous studies with OG in four-repeat telomere sequences that found OG to be highly destabilizing and causing significant reorientation of the fold. When taking a wider view of the human telomere sequence and considering additional repeats, we found OG to cause minimal impact on the structure. The plasticity of this repeat sequence addresses how OG concentrations can increase in telomeres without immediate telomere instability or attrition.

更新日期：2015-12-29

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