Mercuric ion inhibition of eukaryotic transcription factor binding to DNA 1 1Abbreviations: TFIIIA, transcription factor A for RNA polymerase III; Cys2His2, two cysteine and two histidine amino acids; ICR, internal control region; S, sedimentation constant; DNase I, deoxyribonuclease I; DEAE, diethylaminoethyl; RNase A, ribonuclease A; and SV40, simian virus 40

Rodgers, Justin S.; Hocker, James R.; Hanas, Rushie J.; Nwosu, Evelyn C; Hanas, Jay S.

doi:10.1016/s0006-2952(01)00629-3

Cited by 32 publications

(5 citation statements)

References 34 publications

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“…The faster migration of the PLII protein, observed in the SDS-PAGE, was already reported for this protein after the exposure of M. galloprovincialis to CdCl 2 [ 43 ]. All these effects could be the consequence of the well-known observation that chromatin-associated proteins are possible targets of mercury ion toxicity, because studies of rodent tissue culture cells exposed to HgCl 2 have shown that mercury ions concentrate in cell nuclei and associate with chromatin [ 44 ]. In addition, it is well-known that Hg ions can also modulate the activity of certain proteins by changing their conformation.…”

Section: Discussionmentioning

confidence: 99%

New Insights into Alterations in PL Proteins Affecting Their Binding to DNA after Exposure of Mytilus galloprovincialis to Mercury—A Possible Risk to Sperm Chromatin Structure?

Lettieri

Notariale

Carusone

et al. 2021

IJMS

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Mercury (Hg) is a highly toxic and widespread pollutant. We previously reported that the exposure of Mytilus galloprovincialis for 24 h to doses of HgCl2 similar to those found in seawater (range 1–100 pM) produced alterations in the properties of protamine-like (PL) proteins that rendered them unable to bind and protect DNA from oxidative damage. In the present work, to deepen our studies, we analyzed PL proteins by turbidimetry and fluorescence spectroscopy and performed salt-induced release analyses of these proteins from sperm nuclei after the exposure of mussels to HgCl2 at the same doses. Turbidity assays indicated that mercury, at these doses, induced PL protein aggregates, whereas fluorescence spectroscopy measurements showed mercury-induced conformational changes. Indeed, the mobility of the PLII band changed in sodium dodecyl sulphate-polyacrylamide gel electrophoresis, particularly after exposure to 10-pM HgCl2, confirming the mercury-induced structural rearrangement. Finally, exposure to HgCl2 at all doses produced alterations in PL-DNA binding, detectable by DNA absorption spectra after the PL protein addition and by a decreased release of PLII and PLIII from the sperm nuclei. In conclusion, in this paper, we reported Hg-induced PL protein alterations that could adversely affect mussel reproductive activity, providing an insight into the molecular mechanism of Hg-related infertility.

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Section: Discussionmentioning

confidence: 99%

New Insights into Alterations in PL Proteins Affecting Their Binding to DNA after Exposure of Mytilus galloprovincialis to Mercury—A Possible Risk to Sperm Chromatin Structure?

Lettieri

Notariale

Carusone

et al. 2021

IJMS

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“…In this context, Hg(II) at concentrations up to 15 mM rapidly inhibits the DNA binding of the chromatin-associated TFIIIA and Sp1, assayed by DNase I protection. 119 However, an earlier report indicated that lower concentrations of Hg(II) (o5 mM) exerted no inhibitory effects. 120 In HL-1 cardiac muscle cells, Hg(II) causes downregulation of GATA-4 mRNA expression.…”

Section: Mercurymentioning

confidence: 97%

Zinc finger proteins as templates for metal ion exchange and ligand reactivity. Chemical and biological consequences

2011

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Zinc finger reactions with inorganic ions and coordination compounds are as diverse as the zinc fingers themselves. Use of metal ions such as Co(2+) and Cd(2+) has given structural, thermodynamic and kinetic information on zinc fingers and zinc-finger-DNA/RNA interactions. It is a general truism that alteration of the coordination sphere in the finger environment will disrupt the recognition with DNA/RNA and this has implications for mechanism of toxicity and carcinogenesis of metal ions. Structural zinc fingers are susceptible to electrophilic attack and the recognition that the coordination sphere of inorganic compounds may be modulated for control of electrophilic attack on zinc fingers raises the possibility of systematic studies of zinc fingers as drug targets using inorganic chemistry. Some inorganic compounds such as those of As(III) and Au(I) may exert their biological effects through inactivation of zinc fingers and novel approaches to specifically attack the zinc-bound ligands using Co(III)-Schiff bases and Platinum(II)-Nucleobase compounds have been proposed. The genomic importance of zinc fingers suggests that the "coordination chemistry" of zinc fingers themselves is ripe for exploration to design new targets for medicinal inorganic chemistry.

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“…[ 69 , 70 , 71 , 72 , 73 , 74 , 75 ] Hg II ions were also found to inhibit the DNA binding activity of the Cys 2 His 2 zinc finger protein transcription factor III A and Sp1 in vitro, although no information on the Hg II coordination was provided. [ 76 , 77 , 78 ] Importantly, the affinity of Hg II towards Rad50 hook models examined in this study was found, not surprisingly, to be significantly higher than the affinity towards Zn II . Taken together, the zinc hook domain could serve as an excellent target for Hg II binding and the resulting genotoxic activity.…”

Section: Resultsmentioning

confidence: 62%

“…In fact, the accumulation of mercury inside the cell nucleus and its association with non‐histone proteins of chromatin after mercury exposure in mice, rats, or in isolated cells, was detected years ago [69–75] . Hg II ions were also found to inhibit the DNA binding activity of the Cys 2 His 2 zinc finger protein transcription factor III A and Sp1 in vitro, although no information on the Hg II coordination was provided [76–78] . Importantly, the affinity of Hg II towards Rad50 hook models examined in this study was found, not surprisingly, to be significantly higher than the affinity towards Zn II .…”

Section: Resultsmentioning

confidence: 69%

An Extremely Stable Interprotein Tetrahedral Hg(Cys)₄ Core Forms in the Zinc Hook Domain of Rad50 Protein at Physiological pH

Łuczkowski

Padjasek

Tran

et al. 2022

Chemistry A European J

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In nature, thiolate-based systems are the primary targets of divalent mercury (Hg II ) toxicity. The formation of Hg (Cys) x cores in catalytic and structural protein centers mediates mercury's toxic effects and ultimately leads to cellular damage. Multiple studies have revealed distinct Hg IIthiolate coordination preferences, among which linear Hg II complexes are the most commonly observed in solution at physiological pH. Trigonal or tetrahedral geometries are formed at basic pH or in tight intraprotein Cys-rich metal sites. So far, no interprotein tetrahedral Hg II complex formed at neutral pH has been reported. Rad50 protein is a part of the multiprotein MRN complex, a major player in DNA damage-repair processes. Its central region consists of a conserved CXXC motif that enables dimerization of two Rad50 molecules by coordinating Zn II . Dimerized motifs form a unique interprotein zinc hook domain (Hk) that is critical for the biological activity of the MRN. Using a series of lengthdifferentiated peptide models of the Pyrococcus furiosus zinc hook domain, we investigated its interaction with Hg II . Using UV-Vis, CD, PAC, and 199 Hg NMR spectroscopies as well as anisotropy decay, we discovered that all Rad50 fragments preferentially form homodimeric Hg(Hk) 2 species with a distorted tetrahedral HgS 4 coordination environment at physiological pH; this is the first example of an interprotein mercury site displaying tetrahedral geometry in solution. At higher Hg II content, monomeric HgHk complexes with linear geometry are formed. The Hg(Cys) 4 core of Rad50 is extremely stable and does not compete with cyanides, NAC, or DTT. Applying ITC, we found that the stability constant of the Rad50 Hg(Hk) 2 complex is approximately three orders of magnitude higher than those of the strongest Hg II complexes known to date.

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Cited by 32 publications

References 34 publications

New Insights into Alterations in PL Proteins Affecting Their Binding to DNA after Exposure of Mytilus galloprovincialis to Mercury—A Possible Risk to Sperm Chromatin Structure?

New Insights into Alterations in PL Proteins Affecting Their Binding to DNA after Exposure of Mytilus galloprovincialis to Mercury—A Possible Risk to Sperm Chromatin Structure?

Zinc finger proteins as templates for metal ion exchange and ligand reactivity. Chemical and biological consequences

An Extremely Stable Interprotein Tetrahedral Hg(Cys)₄ Core Forms in the Zinc Hook Domain of Rad50 Protein at Physiological pH

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Cited by 32 publications

References 34 publications

New Insights into Alterations in PL Proteins Affecting Their Binding to DNA after Exposure of Mytilus galloprovincialis to Mercury—A Possible Risk to Sperm Chromatin Structure?

New Insights into Alterations in PL Proteins Affecting Their Binding to DNA after Exposure of Mytilus galloprovincialis to Mercury—A Possible Risk to Sperm Chromatin Structure?

Zinc finger proteins as templates for metal ion exchange and ligand reactivity. Chemical and biological consequences

An Extremely Stable Interprotein Tetrahedral Hg(Cys)4 Core Forms in the Zinc Hook Domain of Rad50 Protein at Physiological pH

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An Extremely Stable Interprotein Tetrahedral Hg(Cys)₄ Core Forms in the Zinc Hook Domain of Rad50 Protein at Physiological pH