DNA repair glycosylases with a [4Fe–4S] cluster: A redox cofactor for DNA-mediated charge transport?

Boal, Amie K.; Yavin, Eylon; Barton, Jacqueline K.

doi:10.1016/j.jinorgbio.2007.05.001

Cited by 49 publications

(42 citation statements)

References 79 publications

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“…The bacterial DinG helicase is active only when its H 2 O 2 -resistant cluster is oxidized (50). In the case of the base excision repair enzymes, it was shown that oxidized MutY has a greater affinity for DNA and that DNAbound MutY can be reduced by another distally bound MutY through DNA-mediated charge transfer (51). Thus, all known Fe-S proteins that control their activity through the redox state of the Fe-S cluster are involved in the cellular response after an oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Redox Control of the Human Iron-Sulfur Repair Protein MitoNEET Activity via Its Iron-Sulfur Cluster

Golinelli-Cohen

Lescop

Mons

et al. 2016

Journal of Biological Chemistry

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Human mitoNEET (mNT) is the first identified Fe-S protein of the mammalian outer mitochondrial membrane. Recently, mNT has been implicated in cytosolic Fe-S repair of a key regulator of cellular iron homeostasis. Here, we aimed to decipher the mechanism by which mNT triggers its Fe-S repair capacity. By using tightly controlled reactions combined with complementary spectroscopic approaches, we have determined the differential roles played by both the redox state of the mNT cluster and dioxygen in cluster transfer and protein stability. We unambiguously demonstrated that only the oxidized state of the mNT cluster triggers cluster transfer to a generic acceptor protein and that dioxygen is neither required for the cluster transfer reaction nor does it affect the transfer rate. In the absence of apo-acceptors, a large fraction of the oxidized holo-mNT form is converted back to reduced holo-mNT under low oxygen tension. Reduced holo-mNT, which holds a [2Fe-2S] ؉ with a global protein fold similar to that of the oxidized form is, by contrast, resistant in losing its cluster or in transferring it. Our findings thus demonstrate that mNT uses an iron-based redox switch mechanism to regulate the transfer of its cluster. The oxidized state is the "active state," which reacts promptly to initiate Fe-S transfer independently of dioxygen, whereas the reduced state is a "dormant form." Finally, we propose that the redox-sensing function of mNT is a key component of the cellular adaptive response to help stress-sensitive Fe-S proteins recover from oxidative injury.MitoNEET (mNT) 5 is an Fe-S protein of the mammalian outer mitochondrial membrane previously identified as a target of the type II diabetes drug pioglitazone (1). This 13-kDa protein is anchored to the outer mitochondrial membrane by its 32-amino acid N terminus with the major part of the protein, including the C-terminal [2Fe-2S] binding domain, located in the cytosol (2). In vivo, the biological activity of mNT has been linked to the regulation of iron/reactive oxygen species homeostasis in vivo (3, 4) to cell proliferation in human breast cancer (5) and to the regulation of lipid and glucose metabolism (4).Crystallographic studies of the soluble form of mNT (mNT ) revealed that the protein dimerizes and accommodates one [2Fe-2S] cluster per monomer coordinated by three cysteines (Cys-72, Cys-74, and Cys-83) and one histidine (His-87) in a CDGSH domain (6 -9). The cluster is redox-active with a midpoint redox potential of roughly 0 mV at pH 7 (10), and its lability depends on its redox state and on the pH (9, 11). mNT is also able to transfer its cluster in vitro to a cyanobacterial (12) and Escherichia coli apoferredoxin or to human ironregulatory protein-1 (IRP-1)/cytosolic aconitase (13). Recently, it has been proposed that mNT plays a specific role in cytosolic Fe-S cluster repair of IRP-1, a key regulator of cellular iron homeostasis in mammalian cells (13).It has been pointed out previously (12) that oxidation of the mNT cluster is necessary to trigger Fe-S ...

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Section: Discussionmentioning

confidence: 99%

Redox Control of the Human Iron-Sulfur Repair Protein MitoNEET Activity via Its Iron-Sulfur Cluster

Golinelli-Cohen

Lescop

Mons

et al. 2016

Journal of Biological Chemistry

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“…DNA binding thus changes the redox properties of the enzymes from being similar to ferredoxins to instead resembling high potential iron proteins. Based on these data, we have proposed a redox role for the [4Fe-4S] clusters in long-range DNA-mediated signaling as a first step in detecting damaged sites that are to be repaired in the genome (32)(33)(34)38). Our ability to alter the redox states of these proteins in a DNA-mediated manner further suggests that DNA may be a medium through which oxidation/ reduction reactions occur.…”

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confidence: 86%

DNA binding shifts the redox potential of the transcription factor SoxR

Gorodetsky

Dietrich²,

Lee

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Electrochemistry measurements on DNA-modified electrodes are used to probe the effects of binding to DNA on the redox potential of SoxR, a transcription factor that contains a [2Fe-2S] cluster and is activated through oxidation. A DNA-bound potential of ؉200 mV versus NHE (normal hydrogen electrode) is found for SoxR isolated from Escherichia coli and Pseudomonas aeruginosa. This potential value corresponds to a dramatic shift of ؉490 mV versus values found in the absence of DNA. Using Redmond red as a covalently bound redox reporter affixed above the SoxR binding site, we also see, associated with SoxR binding, an attenuation in the Redmond red signal compared with that for Redmond red attached below the SoxR binding site. This observation is consistent with a SoxRbinding-induced structural distortion in the DNA base stack that inhibits DNA-mediated charge transport to the Redmond red probe. The dramatic shift in potential for DNA-bound SoxR compared with the free form is thus reconciled based on a high-energy conformational change in the SoxR-DNA complex. The substantial positive shift in potential for DNA-bound SoxR furthermore indicates that, in the reducing intracellular environment, DNA-bound SoxR is primarily in the reduced form; the activation of DNA-bound SoxR would then be limited to strong oxidants, making SoxR an effective sensor for oxidative stress. These results more generally underscore the importance of using DNA electrochemistry to determine DNA-bound potentials for redox-sensitive transcription factors because such binding can dramatically affect this key protein property.

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“…For this purpose, we have utilized noncovalent 104,105,110-116 and covalent 106,117-125 redox probes as well as DNA-binding proteins that are redox-active. 126-133 These different probes are illustrated in Fig. 4.…”

Section: Dna Ct On Surfacesmentioning

confidence: 99%

Solution, surface, and single molecule platforms for the study of DNA-mediated charge transport

Muren

Olmon

Barton

2012

Phys. Chem. Chem. Phys.

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The structural core of DNA, a continuous stack of aromatic heterocycles, the base pairs, which extends down the helical axis, gives rise to the fascinating electronic properties of this molecule that is so critical for life. Our laboratory and others have developed diverse experimental platforms to investigate the capacity of DNA to conduct charge, termed DNA-mediated charge transport (DNA CT). Here, we present an overview of DNA CT experiments in solution, on surfaces, and with single molecules that collectively provide a broad and consistent perspective on the essential characteristics of this chemistry. DNA CT can proceed over long molecular distances but is remarkably sensitive to perturbations in base pair stacking. We discuss how this foundation, built with data from diverse platforms, can be used both to inform a mechanistic description of DNA CT and to inspire the next platforms for its study: living organisms and molecular electronics.

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DNA repair glycosylases with a [4Fe–4S] cluster: A redox cofactor for DNA-mediated charge transport?

Cited by 49 publications

References 79 publications

Redox Control of the Human Iron-Sulfur Repair Protein MitoNEET Activity via Its Iron-Sulfur Cluster

Redox Control of the Human Iron-Sulfur Repair Protein MitoNEET Activity via Its Iron-Sulfur Cluster

DNA binding shifts the redox potential of the transcription factor SoxR

Solution, surface, and single molecule platforms for the study of DNA-mediated charge transport

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