Redox Signaling through DNA

O’Brien, Elizabeth; Silva, Rebekah M.B.; Barton, Jacqueline K.

doi:10.1002/ijch.201600022

Cited by 19 publications

(29 citation statements)

References 169 publications

(420 reference statements)

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“…21 Given the low copy number of unique DNA-processing [4Fe4S] enzymes, ranging from 500 to as low as 10 per cell, 22,23 and the vast number of DNA lesions, we have proposed that these proteins aid one another through signaling using DNA-mediated charge transport (CT) between their [4Fe4S] clusters to search for and locate DNA damage sites more efficiently. 21,24,25 …”

Section: Introductionmentioning

confidence: 99%

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The Oxidation State of [4Fe4S] Clusters Modulates the DNA-Binding Affinity of DNA Repair Proteins

2017

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A central question important to understanding DNA repair is how certain proteins are able to search for, detect, and fix DNA damage on a biologically relevant timescale. A feature of many base excision repair proteins is that they contain [4Fe4S] clusters that may aid their search for lesions. In this report, we establish the importance of the oxidation state of the redox-active [4Fe4S] cluster in the DNA damage detection process. We utilize DNA-modified electrodes to generate repair proteins with [4Fe4S] clusters in the 2+ and 3+ states by bulk electrolysis under an O2-free atmosphere. Anaerobic microscale thermophoresis results indicate that proteins carrying [4Fe4S]3+ clusters bind to DNA 550 times more tightly than those with [4Fe4S]2+ clusters. The measured increase in DNA-binding affinity matches the calculated affinity change associated with the redox potential shift observed for [4Fe4S] cluster proteins upon binding to DNA. We further devise an electrostatic model that shows this change in DNA-binding affinity of these proteins can be fully explained by the differences in electrostatic interactions between DNA and the [4Fe4S] cluster in the reduced versus oxidized state. We then utilize atomic force microscopy (AFM) to demonstrate that the redox state of the [4Fe4S] clusters regulates the ability of two DNA repair proteins, Endonuclease III and DinG, to bind preferentially to DNA duplexes containing a single site of DNA damage (here a base mismatch) which inhibits DNA charge transport. Together, these results show that the reduction and oxidation of [4Fe4S] clusters through DNA-mediated charge transport facilitates long-range signaling between [4Fe4S] repair proteins. The redox-modulated change in DNA-binding affinity regulates the ability of [4Fe4S] repair proteins to collaborate in the lesion detection process.

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Section: Introductionmentioning

confidence: 99%

“…24,25,33 The DNA-mediated redox properties of [4Fe4S] proteins have been established in vitro using biochemical assays and DNA-modified electrodes. These experiments show that the [4Fe4S] cluster within a protein can be reduced to the 2+ state or oxidized to the 3+ state by CT through a DNA duplex.…”

Section: Introductionmentioning

confidence: 99%

The Oxidation State of [4Fe4S] Clusters Modulates the DNA-Binding Affinity of DNA Repair Proteins

2017

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“…These studies have led to a model in which [4Fe4S] base excision repair (BER) proteins with similar DNAbound redox potentials use reversible redox exchanges to signal to one another across the genome, taking advantage of the unique ability of DNA to conduct charge across the π stacked base pairs (bps) in a process known as DNAmediated charge transport (DNA CT)[15, 16]. DNA CT has both a very shallow distance dependence and an exquisite sensitivity to even slight disruptions in base pair stacking, making it an ideal lesion reporter.…”

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confidence: 99%

A human MUTYH variant linking colonic polyposis to redox degradation of the [4Fe4S]2+ cluster

et al. 2018

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The human DNA repair enzyme MUTYH excises mispaired adenine residues in oxidized DNA. Homozygous MUTYH mutations underlie the autosomal, recessive cancer syndrome MUTYHassociated polyposis. We report a MUTYH variant, p.C306W (c.918C>G), with a tryptophan residue in place of native cysteine, that ligates the [4Fe4S] cluster in a patient with colonic polyposis and family history of earlyage colon cancer. In bacterial MutY, the [4Fe4S] cluster is redox active, allowing rapid localization to target lesions by longrange, DNAmediated signalling. In the current study, using DNA electrochemistry, we determine that wildtype MUTYH is similarly redoxactive, but MUTYH C306W undergoes rapid oxidative degradation of its cluster to [3Fe4S]+, with loss of redox signalling. In MUTYH C306W, oxidative cluster degradation leads to decreased DNA binding and enzyme function. This study confirms redox activity in eukaryotic DNA repair proteins and establishes MUTYH C306W as a pathogenic variant, highlighting the essential role of redox signalling by the [4Fe4S] cluster.

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“…Indeed, a whole family of DNA repair enzymes has been found to contain [4Fe4S] clusters, redox cofactors featured commonly in proteins, and many experiments we have carried out support the idea that these repair proteins utilize DNA CT chemistry in their search for lesions within the cell. 5,50 Significant kinks to DNA caused by protein binding, such as the TATA-binding protein, 51 or chemical interactions with molecules such as cisplatin will also disrupt DNA CT. Again, it is the stacking of bases that must be preserved for long-range CT, so that anything that perturbs that base stacking turns off charge transport mediated by DNA.…”

Section: Stacking Is Essential For Dna Ctmentioning

confidence: 99%

Sensing DNA through DNA Charge Transport

2018

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DNA charge transport chemistry involves the migration of charge over long molecular distances through the aromatic base pair stack within the DNA helix. This migration depends upon the intimate coupling of bases stacked one with another, and hence any perturbation in that stacking, through base modifications or protein binding, can be sensed electrically. In this review, we describe the many ways DNA charge transport chemistry has been utilized to sense changes in DNA, including the presence of lesions, mismatches, DNA-binding proteins, protein activity, and even reactions under weak magnetic fields. Charge transport chemistry is remarkable in its ability to sense the integrity of DNA.

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Redox Signaling through DNA

Cited by 19 publications

References 169 publications

The Oxidation State of [4Fe4S] Clusters Modulates the DNA-Binding Affinity of DNA Repair Proteins

The Oxidation State of [4Fe4S] Clusters Modulates the DNA-Binding Affinity of DNA Repair Proteins

A human MUTYH variant linking colonic polyposis to redox degradation of the [4Fe4S]2+ cluster

Sensing DNA through DNA Charge Transport

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