A role for DNA-mediated charge transport in regulating p53: Oxidation of the DNA-bound protein from a distance

Augustyn, Katherine E.; Merino, Edward J.; Barton, Jacqueline K.

doi:10.1073/pnas.0709326104

Cited by 49 publications

(69 citation statements)

References 34 publications

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“…There are many oxidants in the cellular milieu, and the level of oxidative stress will govern the proportion of oxidized protein. Indeed, we have shown that these proteins (22) and others (27) can be oxidized by guanine radicals, the first genomic signal of oxidative stress (28), via DNA-mediated CT.…”

Section: Resultsmentioning

confidence: 99%

Redox signaling between DNA repair proteins for efficient lesion detection

Boal

Genereux

Sontz

et al. 2009

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

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120

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Base excision repair (BER) enzymes maintain the integrity of the genome, and in humans, BER mutations are associated with cancer. Given the remarkable sensitivity of DNA-mediated charge transport (CT) to mismatched and damaged base pairs, we have proposed that DNA repair glycosylases (EndoIII and MutY) containing a redox-active [4Fe4S] cluster could use DNA CT in signaling one another to search cooperatively for damage in the genome. Here, we examine this model, where we estimate that electron transfers over a few hundred base pairs are sufficient for rapid interrogation of the full genome. Using atomic force microscopy, we found a redistribution of repair proteins onto DNA strands containing a single base mismatch, consistent with our model for CT scanning. We also demonstrated in Escherichia coli a cooperativity between EndoIII and MutY that is predicted by the CT scanning model. This relationship does not require the enzymatic activity of the glycosylase. Y82A EndoIII, a mutation that renders the protein deficient in DNA-mediated CT, however, inhibits cooperativity between MutY and EndoIII. These results illustrate how repair proteins might efficiently locate DNA lesions and point to a biological role for DNA-mediated CT within the cell.DNA charge transport ͉ DNA damage ͉ iron-sulfur proteins ͉ oxidative stress

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Section: Resultsmentioning

confidence: 99%

Redox signaling between DNA repair proteins for efficient lesion detection

Boal

Genereux

Sontz

et al. 2009

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

Self Cite

120

294

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“…3A, B and data not shown) oxidation of cellular thiols should be involved. TP53 is one of the multiple cellular targets regulated by thiol modification 34,35 and we have previously observed a significant role of TP53 of dormancy. 29 However, TP53 alone cannot account for the importance of the redox imbalance since its impact on the number of dormant cells is only modest.…”

Section: Bmp4 (mentioning

confidence: 86%

SMAD signaling and redox imbalance cooperate to induce prostate cancer cell dormancy

et al. 2015

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Abbreviations: BSO, buthionine sulfoximine; CE, cloning efficiency; DMEM-FCS, Dulbecco Modified Essential Medium supplemented with 10% Fetal Calf Serum and penicillin-streptomycin; LD_hyper, low cell density condition in DMEM-FCS medium; LD_hypo, low cell density condition in hypotonic medium made by addition of 25% water to DMEM-FCS; MD_hypo, medium cell density condition in hypotonic medium made by addition of 25% water to DMEM-FCS; MD_hyper, medium cell density condition in DMEM-FCS medium (slightly hypertonic); NAM, Normalized Averaging Method; ARM, Averaging Ratio Method.Metastasis involves the dissemination of single or small clumps of cancer cells through blood or lymphatic vessels and their extravasation into distant organs. Despite the strong regulation of metastases development by a cell dormancy phenomenon, the dormant state of cancer cells remains poorly characterized due to the difficulty of in vivo studies. We have recently shown in vitro that clonogenicity of prostate cancer cells is regulated by a dormancy phenomenon that is strongly induced when cells are cultured both at low cell density and in a slightly hypertonic medium. Here, we characterized by RT-qPCR a genetic expression signature of this dormant state which combines the presence of both stemness and differentiation markers. We showed that both TFGb/BMP signaling and redox imbalance are required for the full induction of this dormancy signature and cell quiescence. Moreover, reconstruction experiments showed that TFGb/BMP signaling and redox imbalance are sufficient to generate a pattern of genetic expression displaying all characteristic features of the dormancy signature. Finally, we observed that low cell density was sufficient to activate TGFb/BMP signaling and to generate a slight redox imbalance thus priming cells for dormancy that can be attained with a co-stimulus like hypertonicity, most likely through an increased redox imbalance. The identification of a dual regulation of dormancy provides a framework for the interpretation of previous reports showing a restricted ability of BMP signaling to regulate cancer cell dormancy in vivo and draws attention on the role of oxidative stress in the metastatic process.

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“…Indeed, XPD may utilize DNA-mediated CT to signal its presence and perhaps to "call off" other proteins from other repair pathways. Various DNA-binding proteins, such as those involved in repair and other DNA transactions, have been found to contain iron-sulfur domains and other redox cofactors (50)(51)(52)(53). DNAmediated signaling among DNA-binding proteins that are involved in maintaining the integrity of the genome allows a coordination of repair, transcription, and replication processes.…”

Section: Discussionmentioning

confidence: 99%

DNA charge transport as a first step in coordinating the detection of lesions by repair proteins

Sontz

Mui

Fuss

et al. 2012

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

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127

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Damaged bases in DNA are known to lead to errors in replication and transcription, compromising the integrity of the genome. We have proposed a model where repair proteins containing redoxactive [4Fe-4S] clusters utilize DNA charge transport (CT) as a first step in finding lesions. In this model, the population of sites to search is reduced by a localization of protein in the vicinity of lesions. Here, we examine this model using single-molecule atomic force microscopy (AFM). XPD, a 5′-3′ helicase involved in nucleotide excision repair, contains a [4Fe-4S] cluster and exhibits a DNAbound redox potential that is physiologically relevant. In AFM studies, we observe the redistribution of XPD onto kilobase DNA strands containing a single base mismatch, which is not a specific substrate for XPD but, like a lesion, inhibits CT. We further provide evidence for DNA-mediated signaling between XPD and Endonuclease III (EndoIII), a base excision repair glycosylase that also contains a [4Fe-4S] cluster. When XPD and EndoIII are mixed together, they coordinate in relocalizing onto the mismatched strand. However, when a CT-deficient mutant of either repair protein is combined with the CT-proficient repair partner, no relocalization occurs. These data not only indicate a general link between the ability of a repair protein to carry out DNA CT and its ability to redistribute onto DNA strands near lesions but also provide evidence for coordinated DNA CT between different repair proteins in their search for damage in the genome.DNA electron transfer | iron-sulfur clusters | oxidative damage

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A role for DNA-mediated charge transport in regulating p53: Oxidation of the DNA-bound protein from a distance

Cited by 49 publications

References 34 publications

Redox signaling between DNA repair proteins for efficient lesion detection

Redox signaling between DNA repair proteins for efficient lesion detection

SMAD signaling and redox imbalance cooperate to induce prostate cancer cell dormancy

DNA charge transport as a first step in coordinating the detection of lesions by repair proteins

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