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Zinc-Finger Proteins in Health and Disease
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Zinc-Finger Proteins in Health and Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Genetics and Genomics".

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 23472

Special Issue Editors

Dr. Amelia Casamassimi

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Guest Editor
Department of Precision Medicine, University of Campania Luigi Vanvitelli, 80138 Naples, Italy
Interests: cancer; PRDM genes; transcriptional regulation
Special Issues, Collections and Topics in MDPI journals
Dr. Monica Rienzo

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Co-Guest Editor
Department of Environmental, Biological, and Pharmaceutical Sciences and Technologies, University of Campania “Luigi Vanvitelli”, 81100 Caserta, Italy
Interests: PRDM genes; cancer; transcriptional regulation
Special Issues, Collections and Topics in MDPI journals
Dr. Ciro Abbondanza

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Co-Guest Editor
Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via L. De Crecchio, 80138 Naples, Italy
Interests: PRDM genes; steroid receptors; cancers
Special Issues, Collections and Topics in MDPI journals
Dr. Erika Zazzo

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Co-Guest Editor
Department of Medicine and Health Science, University of Molise, Campobasso, Italy
Interests: PRDM genes; cancers; signal transduction; cancer; cell cycle; apoptosis; androgens; estrogens; prostate cancer; breast cancer; oxidative stress; steroid receptors; testicular germ cell tumors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Proteins containing Zinc-finger domain(s) (ZFP) are able to mediate the interaction with DNA, RNA, and other proteins. They are implicated in transcriptional regulation, ubiquitin-mediated protein degradation, signal transduction, DNA repair, cell migration, and numerous other processes. Besides, many of these proteins function through epigenetic modifications such as DNA methylation and histone modifications, which regulate transcription in physiological and pathological conditions.

The number and the type of zinc fingers in a single protein can be highly variable, thus allowing also a great variability of targets. The Cys2His2 type represents the classical and most abundant zinc finger motif, and it is present in over 700 proteins in humans, with many of them functioning as transcription factors. Among them, the well-known CTCF protein, an important regulator of chromatin organization, contains 11 highly conserved zinc-finger motifs and it plays a central role in the control of gene expression by stabilizing the enhancer-promoter interaction.

Of note, these proteins often contain multiple additional domains other than zinc-fingers. Indeed, in metazoan zinc-finger domains are rarely found alone and usually form tandem arrays combined with different domains thus further increasing their complexity and potential functions. These domains include Krüppel-associated box (KRAB), SCAN, the zinc finger-associated domain (ZAD) among the others. Likewise, members of the positive regulatory domain (PRDM) family gene are characterized by a PR domain, related to the SET methyltransferase domain, and multiple zinc fingers motifs. PRDM proteins are able to modulate the expression of target genes by modifying the chromatin structure either directly, through their intrinsic methyltransferase activity, or indirectly, through the recruitment of specific chromatin remodeling complexes. The PRDM gene family is involved in a broad spectrum of biological processes, including proliferation and differentiation control, cell cycle progression, stemness and maintenance of immune cell homeostasis, being implicated in the transduction of several signals. Remarkably, given this wide range of functions, their disruption may contribute to the onset and progression of several human diseases. Similarly, other ZFPs, such as GATA family proteins and Nuclear Receptors among the others, have been established to play a pathophysiological role in humans.

We invite authors to submit both original research articles and review articles that cover recent research advances in the understanding of the molecular mechanisms of transcriptional regulation and main processes controlled by ZFPs during the development, cell homeostasis maintenance, as well as in the onset and progression of human disease.

Dr. Amelia Casamassimi
Guest Editor
Dr. Monica Rienzo
Prof. Dr. Ciro Abbondanza
Dr. Erika Di Zazzo
Co-Guest Editors

Manuscript Submission Information

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Keywords

  • Zinc-finger domain
  • CTCF
  • PRDM family
  • GATA family
  • Nuclear receptors
  • Human diseases
  • Gene expression regulation
  • Epigenetic modifications

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Published Papers (6 papers)

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Research

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16 pages, 2664 KiB  
Article
Copper (I) or (II) Replacement of the Structural Zinc Ion in the Prokaryotic Zinc Finger Ros Does Not Result in a Functional Domain
by Martina Dragone, Rinaldo Grazioso, Gianluca D’Abrosca, Ilaria Baglivo, Rosa Iacovino, Sabrina Esposito, Antonella Paladino, Paolo V. Pedone, Luigi Russo, Roberto Fattorusso, Gaetano Malgieri and Carla Isernia
Int. J. Mol. Sci. 2022, 23(19), 11010; https://doi.org/10.3390/ijms231911010 - 20 Sep 2022
Cited by 4 | Viewed by 1895
Abstract
A strict interplay is known to involve copper and zinc in many cellular processes. For this reason, the results of copper’s interaction with zinc binding proteins are of great interest. For instance, copper interferences with the DNA-binding activity of zinc finger proteins are [...] Read more.
A strict interplay is known to involve copper and zinc in many cellular processes. For this reason, the results of copper’s interaction with zinc binding proteins are of great interest. For instance, copper interferences with the DNA-binding activity of zinc finger proteins are associated with the development of a variety of diseases. The biological impact of copper depends on the chemical properties of its two common oxidation states (Cu(I) and Cu(II)). In this framework, following the attention addressed to unveil the effect of metal ion replacement in zinc fingers and in zinc-containing proteins, we explore the effects of the Zn(II) to Cu(I) or Cu(II) replacement in the prokaryotic zinc finger domain. The prokaryotic zinc finger protein Ros, involved in the horizontal transfer of genes from A. tumefaciens to a host plant infected by it, belongs to a family of proteins, namely Ros/MucR, whose members have been recognized in different bacteria symbionts and pathogens of mammals and plants. Interestingly, the amino acids of the coordination sphere are poorly conserved in most of these proteins, although their sequence identity can be very high. In fact, some members of this family of proteins do not bind zinc or any other metal, but assume a 3D structure similar to that of Ros with the residues replacing the zinc ligands, forming a network of hydrogen bonds and hydrophobic interactions that surrogates the Zn-coordinating role. These peculiar features of the Ros ZF domain prompted us to study the metal ion replacement with ions that have different electronic configuration and ionic radius. The protein was intensely studied as a perfectly suited model of a metal-binding protein to study the effects of the metal ion replacement; it appeared to tolerate the Zn to Cd substitution, but not the replacement of the wildtype metal by Ni(II), Pb(II) and Hg(II). The structural characterization reported here gives a high-resolution description of the interaction of copper with Ros, demonstrating that copper, in both oxidation states, binds the protein, but the replacement does not give rise to a functional domain. Full article
(This article belongs to the Special Issue Zinc-Finger Proteins in Health and Disease)
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15 pages, 2672 KiB  
Article
Engineered Zinc Finger Protein Targeting 2LTR Inhibits HIV Integration in Hematopoietic Stem and Progenitor Cell-Derived Macrophages: In Vitro Study
by Koollawat Chupradit, Wannisa Khamaikawin, Supachai Sakkhachornphop, Chaniporn Puaninta, Bruce E. Torbett, Suparerk Borwornpinyo, Suradej Hongeng, Methichit Wattanapanitch and Chatchai Tayapiwatana
Int. J. Mol. Sci. 2022, 23(4), 2331; https://doi.org/10.3390/ijms23042331 - 19 Feb 2022
Cited by 3 | Viewed by 3041
Abstract
Human hematopoietic stem/progenitor cell (HSPC)-based gene therapy is a promising direction for curing HIV-1-infected individuals. The zinc finger protein (2LTRZFP) designed to target the 2-LTR-circle junction of HIV-1 cDNA was previously reported as an intracellular antiviral molecular scaffold that prevents HIV integration. Here, [...] Read more.
Human hematopoietic stem/progenitor cell (HSPC)-based gene therapy is a promising direction for curing HIV-1-infected individuals. The zinc finger protein (2LTRZFP) designed to target the 2-LTR-circle junction of HIV-1 cDNA was previously reported as an intracellular antiviral molecular scaffold that prevents HIV integration. Here, we elucidate the efficacy and safety of using 2LTRZFP in human CD34+ HSPCs. We transduced 2LTRZFP which has the mCherry tag (2LTRZFPmCherry) into human CD34+ HSPCs using a lentiviral vector. The 2LTRZFPmCherry-transduced HSPCs were subsequently differentiated into macrophages. The expression levels of pro-apoptotic proteins of the 2LTRZFPmCherry-transduced HSPCs showed no significant difference from those of the non-transduced control. Furthermore, the 2LTRZFPmCherry-transduced HSPCs were successfully differentiated into mature macrophages, which had normal phagocytic function. The cytokine secretion assay demonstrated that 2LTRZFPmCherry-transduced CD34+ derived macrophages promoted the polarization towards classically activated (M1) subtypes. More importantly, the 2LTRZFPmCherry transduced cells significantly exhibited resistance to HIV-1 integration in vitro. Our findings demonstrate that the 2LTRZFPmCherry-transduced macrophages were found to be functionally and phenotypically normal, with no adverse effects of the anti-HIV-1 scaffold. Our data suggest that the anti-HIV-1 integrase scaffold is a promising antiviral molecule that could be applied to human CD34+ HSPC-based gene therapy for AIDS patients. Full article
(This article belongs to the Special Issue Zinc-Finger Proteins in Health and Disease)
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29 pages, 6919 KiB  
Article
A Multi-Omics Network of a Seven-Gene Prognostic Signature for Non-Small Cell Lung Cancer
by Qing Ye, Brianne Falatovich, Salvi Singh, Alexey V. Ivanov, Timothy D. Eubank and Nancy Lan Guo
Int. J. Mol. Sci. 2022, 23(1), 219; https://doi.org/10.3390/ijms23010219 - 25 Dec 2021
Cited by 10 | Viewed by 4752
Abstract
There is an unmet clinical need to identify patients with early-stage non-small cell lung cancer (NSCLC) who are likely to develop recurrence and to predict their therapeutic responses. Our previous study developed a qRT-PCR-based seven-gene microfluidic assay to predict the recurrence risk and [...] Read more.
There is an unmet clinical need to identify patients with early-stage non-small cell lung cancer (NSCLC) who are likely to develop recurrence and to predict their therapeutic responses. Our previous study developed a qRT-PCR-based seven-gene microfluidic assay to predict the recurrence risk and the clinical benefits of chemotherapy. This study showed it was feasible to apply this seven-gene panel in RNA sequencing profiles of The Cancer Genome Atlas (TCGA) NSCLC patients (n = 923) in randomly partitioned feasibility-training and validation sets (p < 0.05, Kaplan–Meier analysis). Using Boolean implication networks, DNA copy number variation-mediated transcriptional regulatory network of the seven-gene signature was identified in multiple NSCLC cohorts (n = 371). The multi-omics network genes, including PD-L1, were significantly correlated with immune infiltration and drug response to 10 commonly used drugs for treating NSCLC. ZNF71 protein expression was positively correlated with epithelial markers and was negatively correlated with mesenchymal markers in NSCLC cell lines in Western blots. PI3K was identified as a relevant pathway of proliferation networks involving ZNF71 and its isoforms formulated with CRISPR-Cas9 and RNA interference (RNAi) profiles. Based on the gene expression of the multi-omics network, repositioning drugs were identified for NSCLC treatment. Full article
(This article belongs to the Special Issue Zinc-Finger Proteins in Health and Disease)
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23 pages, 6288 KiB  
Article
ZNF521 Enhances MLL-AF9-Dependent Hematopoietic Stem Cell Transformation in Acute Myeloid Leukemias by Altering the Gene Expression Landscape
by Emanuela Chiarella, Annamaria Aloisio, Stefania Scicchitano, Katia Todoerti, Emanuela G. Cosentino, Daniela Lico, Antonino Neri, Nicola Amodio, Heather Mandy Bond and Maria Mesuraca
Int. J. Mol. Sci. 2021, 22(19), 10814; https://doi.org/10.3390/ijms221910814 - 6 Oct 2021
Cited by 12 | Viewed by 3356
Abstract
Leukemias derived from the MLL-AF9 rearrangement rely on dysfunctional transcriptional networks. ZNF521, a transcription co-factor implicated in the control of hematopoiesis, has been proposed to sustain leukemic transformation in collaboration with other oncogenes. Here, we demonstrate that ZNF521 mRNA levels correlate with specific [...] Read more.
Leukemias derived from the MLL-AF9 rearrangement rely on dysfunctional transcriptional networks. ZNF521, a transcription co-factor implicated in the control of hematopoiesis, has been proposed to sustain leukemic transformation in collaboration with other oncogenes. Here, we demonstrate that ZNF521 mRNA levels correlate with specific genetic aberrations: in particular, the highest expression is observed in AMLs bearing MLL rearrangements, while the lowest is detected in AMLs with FLT3-ITD, NPM1, or CEBPα double mutations. In cord blood-derived CD34+ cells, enforced expression of ZNF521 provides a significant proliferative advantage and enhances MLL-AF9 effects on the induction of proliferation and the expansion of leukemic progenitor cells. Transcriptome analysis of primary CD34+ cultures displayed subsets of genes up-regulated by MLL-AF9 or ZNF521 single transgene overexpression as well as in MLL-AF9/ZNF521 combinations, at either the early or late time points of an in vitro leukemogenesis model. The silencing of ZNF521 in the MLL-AF9 + THP-1 cell line coherently results in an impairment of growth and clonogenicity, recapitulating the effects observed in primary cells. Taken together, these results underscore a role for ZNF521 in sustaining the self-renewal of the immature AML compartment, most likely through the perturbation of the gene expression landscape, which ultimately favors the expansion of MLL-AF9-transformed leukemic clones. Full article
(This article belongs to the Special Issue Zinc-Finger Proteins in Health and Disease)
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Review

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23 pages, 1614 KiB  
Review
Host and Viral Zinc-Finger Proteins in COVID-19
by Sabrina Esposito, Gianluca D’Abrosca, Anna Antolak, Paolo Vincenzo Pedone, Carla Isernia and Gaetano Malgieri
Int. J. Mol. Sci. 2022, 23(7), 3711; https://doi.org/10.3390/ijms23073711 - 28 Mar 2022
Cited by 11 | Viewed by 4225
Abstract
An unprecedented effort to tackle the ongoing COVID-19 pandemic has characterized the activity of the global scientific community over the last two years. Hundreds of published studies have focused on the comprehension of the immune response to the virus and on the definition [...] Read more.
An unprecedented effort to tackle the ongoing COVID-19 pandemic has characterized the activity of the global scientific community over the last two years. Hundreds of published studies have focused on the comprehension of the immune response to the virus and on the definition of the functional role of SARS-CoV-2 proteins. Proteins containing zinc fingers, both belonging to SARS-CoV-2 or to the host, play critical roles in COVID-19 participating in antiviral defenses and regulation of viral life cycle. Differentially expressed zinc finger proteins and their distinct activities could thus be important in determining the severity of the disease and represent important targets for drug development. Therefore, we here review the mechanisms of action of host and viral zinc finger proteins in COVID-19 as a contribution to the comprehension of the disease and also highlight strategies for therapeutic developments. Full article
(This article belongs to the Special Issue Zinc-Finger Proteins in Health and Disease)
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15 pages, 1706 KiB  
Review
PRDM12 in Health and Diseases
by Monica Rienzo, Erika Di Zazzo, Amelia Casamassimi, Patrizia Gazzerro, Giovanni Perini, Maurizio Bifulco and Ciro Abbondanza
Int. J. Mol. Sci. 2021, 22(21), 12030; https://doi.org/10.3390/ijms222112030 - 6 Nov 2021
Cited by 11 | Viewed by 3952
Abstract
PRDM12 is a member of the PRDI-BF1 (positive regulatory domain I-binding factor 1) homologous domain (PRDM)-containing protein family, a subfamily of Kruppel-like zinc finger proteins, controlling key processes in the development of cancer. PRDM12 is expressed in a spatio-temporal manner in neuronal systems [...] Read more.
PRDM12 is a member of the PRDI-BF1 (positive regulatory domain I-binding factor 1) homologous domain (PRDM)-containing protein family, a subfamily of Kruppel-like zinc finger proteins, controlling key processes in the development of cancer. PRDM12 is expressed in a spatio-temporal manner in neuronal systems where it exerts multiple functions. PRDM12 is essential for the neurogenesis initiation and activation of a cascade of downstream pro-neuronal transcription factors in the nociceptive lineage. PRDM12 inactivation, indeed, results in a complete absence of the nociceptive lineage, which is essential for pain perception. Additionally, PRDM12 contributes to the early establishment of anorexigenic neuron identity and the maintenance of high expression levels of pro-opiomelanocortin, which impacts on the program bodyweight homeostasis. PRDMs are commonly involved in cancer, where they act as oncogenes/tumor suppressors in a “Yin and Yang” manner. PRDM12 is not usually expressed in adult normal tissues but its expression is re-activated in several cancer types. However, little information is currently available on PRDM12 expression in cancers and its mechanism of action has not been thoroughly described. In this review, we summarize the recent findings regarding PRDM12 by focusing on four main biological processes: neurogenesis, pain perception, oncogenesis and cell metabolism. Moreover, we wish to highlight the importance of future studies focusing on the PRDM12 signaling pathway(s) and its role in cancer onset and progression. Full article
(This article belongs to the Special Issue Zinc-Finger Proteins in Health and Disease)
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