Functional characterization of iron-substituted neural zinc finger factor 1: metal and DNA binding

Besold, Angelique N.; Lee, Seung-Jae; Michel, Sarah L. J.; Sue, Niall Lue; Cymet, Holly

doi:10.1007/s00775-010-0626-1

Cited by 23 publications

(42 citation statements)

References 34 publications

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“…The physical ability, but catalytic inability, of iron to substitute for zinc is also seen in estrogen receptor zinc finger protein and transcription factor for polymerase III A (32). In contrast, this metal substitution is catalytically functional in the case of neural zinc finger factor 1, tristetraprolin-2D, and GATA-1 zinc finger proteins (14,54,191). It may be possible that the misincorporated iron in eukaryotic top2a could lead to catalytic inactivity of the enzyme or DNA damage.…”

Section: Raomentioning

confidence: 87%

Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications

Rao

2013

Antioxidants & Redox Signaling

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Significance: Iron and topoisomerases are abundant and essential cellular components. Iron is required for several key processes such as DNA synthesis, mitochondrial electron transport, synthesis of heme, and as a co-factor for many redox enzymes. Topoisomerases serve as critical enzymes that resolve topological problems during DNA synthesis, transcription, and repair. Neoplastic cells have higher uptake and utilization of iron, as well as elevated levels of topoisomerase family members. Separately, the chelation of iron and the cytotoxic inhibition of topoisomerase have yielded potent anticancer agents. Recent Advances: The chemotherapeutic drugs doxorubicin and dexrazoxane both chelate iron and target topoisomerase 2 alpha (top2a). Newer chelators such as di-2-pyridylketone-4,4,-dimethyl-3-thiosemicarbazone and thiosemicarbazone -24 have recently been identified as top2a inhibitors. The growing list of agents that appear to chelate iron and inhibit topoisomerases prompts the question of whether and how these two distinct mechanisms might interplay for a cytotoxic chemotherapeutic outcome. Critical Issues: While iron chelation and topoisomerase inhibition each represent mechanistically advantageous anticancer therapeutic strategies, dual targeting agents present an attractive multi-modal opportunity for enhanced anticancer tumor killing and overcoming drug resistance. The commonalities and caveats of dual inhibition are presented in this review. Future Directions: Gaps in knowledge, relevant biomarkers, and strategies for future in vivo studies with dual inhibitors are discussed. Antioxid. Redox Signal. 18, 930-955.

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Section: Raomentioning

confidence: 87%

Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications

Rao

2013

Antioxidants & Redox Signaling

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“…the presence of other cation-binding sites such as the CHY zinc-finger domain, which is capable of binding other metals, including iron (Besold et al, 2010). The fulllength BTS protein also contained significant amounts of zinc metal ion, and deletion of HHE domains resulted in a 5-fold reduction in zinc content associated with BTS DHHE protein (Fig.…”

Section: Hhe Domains Bind Iron and Affect Bts Protein Stabilitymentioning

confidence: 99%

Iron-Binding E3 Ligase Mediates Iron Response in Plants by Targeting Basic Helix-Loop-Helix Transcription Factors

et al. 2014

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Iron uptake and metabolism are tightly regulated in both plants and animals. In Arabidopsis (Arabidopsis thaliana), BRUTUS (BTS), which contains three hemerythrin (HHE) domains and a Really Interesting New Gene (RING) domain, interacts with basic helix-loop-helix transcription factors that are capable of forming heterodimers with POPEYE (PYE), a positive regulator of the iron deficiency response. BTS has been shown to have E3 ligase capacity and to play a role in root growth, rhizosphere acidification, and iron reductase activity in response to iron deprivation. To further characterize the function of this protein, we examined the expression pattern of recombinant ProBTS::b-GLUCURONIDASE and found that it is expressed in developing embryos and other reproductive tissues, corresponding with its apparent role in reproductive growth and development. Our findings also indicate that the interactions between BTS and PYE-like (PYEL) basic helix-loop-helix transcription factors occur within the nucleus and are dependent on the presence of the RING domain. We provide evidence that BTS facilitates 26S proteasome-mediated degradation of PYEL proteins in the absence of iron. We also determined that, upon binding iron at the HHE domains, BTS is destabilized and that this destabilization relies on specific residues within the HHE domains. This study reveals an important and unique mechanism for plant iron homeostasis whereby an E3 ubiquitin ligase may posttranslationally control components of the transcriptional regulatory network involved in the iron deficiency response.

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“…23–26,42,54 In other cases, alternate metal ions have been proposed to substitute for zinc under conditions of zinc depletion (e.g., Fe(II)). 28,31,32,44 …”

Section: Introductionmentioning

confidence: 99%

Cu(I) Disrupts the Structure and Function of the Nonclassical Zinc Finger Protein Tristetraprolin (TTP)

Shimberg

Neu

et al. 2017

Inorg. Chem.

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Tristetraprolin (TTP) is a nonclassical zinc finger (ZF) protein that plays a key role in regulating inflammatory response. TTP regulates cytokines at the mRNA level by binding to AU-rich sequences present at the 3′-untranslated region, forming a complex that is then degraded. TTP contains two conserved CCCH domains with the sequence Cys-X8CysX5CysX3His that are activated to bind RNA when zinc is coordinated. During inflammation, copper levels are elevated, which is associated with increased inflammatory response. A potential target for Cu(I) during inflammation is TTP. To determine whether Cu(I) binds to TTP and how Cu(I) can affect TTP/RNA binding, two TTP constructs were prepared. One construct contained just the first CCCH domain (TTP-1D) and serves as a peptide model for a CCCH domain; the second construct contains both CCCH domains (TTP-2D) and is functional (binds RNA) when Zn(II) is coordinated. Cu(I) binding to TTP-1D was assessed via electronic absorption spectroscopy titrations, and Cu(I) binding to TTP-2D was assessed via both absorption spectroscopy and a spin filter/inductively coupled plasma mass spectrometry (ICP-MS) assay. Cu(I) binds to TTP-1D with a 1:1 stoichiometry and to TTP-2D with a 3:1 stoichiometry. The CD spectrum of Cu(I)-TTP-2D did not exhibit any secondary structure, matching that of apo-TTP-2D, while Zn(II)-TTP-2D exhibited a secondary structure. Measurement of RNA binding via fluorescence anisotropy revealed that Cu(I)-TTP-2D does not bind to the TTP-2D RNA target sequence UUUAUUUAUUU with any measurable affinity, while Zn(II)-TTP-2D binds to this site with nanomolar affinity. Similarly, addition of Cu(I) to the Zn(II)-TTP-2D/RNA complex resulted in inhibition of RNA binding. Together, these data indicate that, while Cu(I) binds to TTP-2D, it does not result in a folded or functional protein and that Cu(I) inhibits Zn(II)-TTP-2D/RNA binding.

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Functional characterization of iron-substituted neural zinc finger factor 1: metal and DNA binding

Cited by 23 publications

References 34 publications

Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications

Iron Chelators with Topoisomerase-Inhibitory Activity and Their Anticancer Applications

Iron-Binding E3 Ligase Mediates Iron Response in Plants by Targeting Basic Helix-Loop-Helix Transcription Factors

Cu(I) Disrupts the Structure and Function of the Nonclassical Zinc Finger Protein Tristetraprolin (TTP)

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