DNA charge transport for sensing and signaling.
DNA charge transport for sensing and signaling.
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DOI：
10.1021/ar3001298
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发表时间：
2012-10-16
影响因子：
18.3
通讯作者：
Barton, Jacqueline K.
中科院分区：
文献类型：
--
作者：
Sontz, Pamela A.;Muren, Natalie B.;Barton, Jacqueline K.
DNA双链体是一种精致的大分子阵列，可存储编码蛋白质和调节途径的遗传信息，但其独特的结构赋予了化学功能，使其也能够介导电荷传输（CT）。我们已经利用不同的平台来探测DNA CT，使用光谱，电化学，甚至遗传学方法。这些研究建立了DNA CT化学的强大功能。只要碱基堆积良好，DNA CT可以在长的分子距离上发生;单碱基错配、DNA损伤和一些使DNA扭结的蛋白质的结合引起的碱基堆积的扰动都有助于抑制DNA CT。值得注意的是，DNA CT的单分子研究表明，只要双链体堆叠良好，基态CT可以在34 nm以上发生;一个单碱基错配抑制CT。DNA双链体是一种有效的传感器的完整性的碱基对堆栈。此外，DNA CT的效率是人们对一堆石墨片的预期，相当于DNA碱基对的堆叠，并且独立于糖-磷酸骨架。由于DNA CT提供了一种从远处进行氧化还原化学反应的方法，我们已经考虑了这种化学反应如何在生物学背景下用于长距离信号传导。我们已经利用我们的化学探针和平台来表征DNA CT也在细胞的情况下。CT可以发生在很长的距离，可能是对特定部位的功能性损伤，并使其他部位免受氧化应激。值得注意的是，激活基因组以响应氧化应激的转录因子也可以通过DNA CT从远处激活。许多蛋白质的工作，以保持基因组的完整性，越来越多地发现他们含有[4Fe-4S]簇，似乎不进行结构或酶的作用。使用电化学方法，我们发现，DNA结合转移的氧化还原电位的集群，激活他们对氧化在生理电位。我们提出了一个模型，描述修复蛋白如何利用DNA CT有效地搜索基因组的病变。重要的是，这些蛋白质中的许多都是低拷贝数的，因此进行性机制不足以解释它们如何在细胞分裂之前发现和修复病变。使用原子力显微镜和遗传分析，我们发现，修复蛋白精通DNA CT能够重新定位在附近的DNA病变，在细胞内，他们合作修复病变。相反，DNA CT缺陷的蛋白质不能重新定位在病变附近，也不能为细胞内参与修复的其他蛋白质提供帮助;此外，这些遗传缺陷与人类蛋白质类似物的疾病有关。随着我们继续解开这种化学并发现更多参与基因组维护的氧化还原辅因子蛋白质，我们正在了解更多关于远程信号和传感的机会，以及更多可能在细胞内发挥关键作用的DNA CT化学的例子。
The DNA duplex is an exquisite macromolecular array that stores genetic information to encode proteins and regulate pathways, but its unique structure imparts chemical function that allows it also to mediate charge transport (CT). We have utilized diverse platforms to probe DNA CT, using spectroscopic, electrochemical, and even genetic methods. These studies have established powerful features of DNA CT chemistry. DNA CT can occur over long molecular distances as long as the bases are well stacked; perturbations in base stacking as arise with single base mismatches, DNA lesions, and the binding of some proteins that kink the DNA, all serve to inhibit DNA CT. Significantly, single molecule studies of DNA CT show that ground state CT can occur over 34 nm as long as the duplex is well stacked; one single base mismatch inhibits CT. The DNA duplex is an effective sensor for the integrity of the base pair stack. Moreover the efficiency of DNA CT is what one would expect for a stack of graphite sheets, equivalent to the stack of DNA base pairs, and independent of the sugar-phosphate backbone. Since DNA CT offers a means to carry out redox chemistry from a distance, we have considered how this chemistry might be used for long range signaling in a biological context. We have taken advantage of our chemical probes and platforms to characterize DNA CT also in the context of the cell. CT can occur over long distances, perhaps funneling damage to particular sites and insulating others from oxidative stress. Significantly, transcription factors that activate the genome to respond to oxidative stress can also be activated from a distance through DNA CT. Numerous proteins work to maintain the integrity of the genome and increasingly they have been found to contain [4Fe-4S] clusters that do not appear to carry out either structural or enzymatic roles. Using electrochemical methods, we find that DNA binding shifts the redox potentials of the clusters, activating them towards oxidation at physiological potentials. We have proposed a model describing how repair proteins may utilize DNA CT to efficiently search the genome for lesions. Importantly, many of these proteins are in low copy number, and thus a processive mechanism is insufficient to explain how they find and repair lesions before the cell divides. Using atomic force microscopy and genetic assays, we find that repair proteins proficient at DNA CT are able to relocalize in the vicinity of DNA lesions and, within the cell, they cooperate in their repair of lesions. Conversely, proteins defective in DNA CT cannot relocalize in the vicinity of lesions and do not provide help to other proteins involved in repair within the cell; moreover these genetic defects are associated with disease in human protein analogues. As we continue to unravel this chemistry and discover more proteins with redox cofactors involved in genome maintenance, we are learning more regarding opportunities for long range signaling and sensing, and more examples of DNA CT chemistry that may play critical roles within the cell.
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影响因子：
2.9
作者：
Merino, Edward J.;Davis, Molly L.;Barton, Jacqueline K.
通讯作者：
Barton, Jacqueline K.
影响因子：
64.8
作者：
Fromme, JC;Banerjee, A;Verdine, GL
通讯作者：
Verdine, GL
DOI：
10.1073/pnas.0906429106
发表时间：
2009-08-11
影响因子：
11.1
作者：
Lee, Paul E.;Demple, Bruce;Barton, Jacqueline K.
通讯作者：
Barton, Jacqueline K.
影响因子：
62.1
作者：
Genereux JC;Barton JK
通讯作者：
Barton JK
影响因子：
14.8
作者：
Netz, Daili J. A.;Stith, Carrie M.;Stuempfig, Martin;Koepf, Gabriele;Vogel, Daniel;Genau, Heide M.;Stodola, Joseph L.;Lill, Roland;Burgers, Peter M. J.;Pierik, Antonio J.
通讯作者：
Pierik, Antonio J.