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Z-DNA and Z-RNA: From Physical Structure to Biological Function
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Z-DNA and Z-RNA: From Physical Structure to Biological Function

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

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 23503

Special Issue Editors

Dr. Alan Herbert

E-Mail Website
Guest Editor
Department of Pharmacology, School of Medicine, University of Auckland, Auckland 6000, New Zealand
Interests: Z-DNA; Z-RNA; ADAR; Zα; flipons; genetics; immunology
Special Issues, Collections and Topics in MDPI journals
Dr. Maria S. Poptsova

E-Mail Website
Guest Editor
Bioifnformatics Lab, Big Data and Information Retrieval School, Faculty of Computer Science, National Research University Higher School of Economics, Moscow, Russia
Interests: non-B DNA structures; Z-DNA; quadruplexes; triplexes; machine learning; deep learning
Special Issues, Collections and Topics in MDPI journals
Dr. Beat Rolf Vögeli

E-Mail Website
Guest Editor
Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Interests: biophysics; nuclear magnetic resonance; protein and nucleic acid structure and dynamics
Special Issues, Collections and Topics in MDPI journals
Dr. Quentin Vicens

E-Mail Website
Guest Editor
Department of Biochemistry and Molecular Genetics, and RNA BioScience Initiative, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
Interests: biochemistry; cryo-electron microscopy; molecular biology; ribosome; RNA structure and folding; structure prediction; X-ray crystallography
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue will commemorate a half-century of discoveries related to the left-handed Z conformations of DNA and RNA. Such innovations are represented by a wide range of disciplines. Starting with the crystallization of Z-DNA in 1979, biophysical and biochemical studies have yielded many unanticipated and fascinating insights into this class of higher energy nucleic acid conformations.

Recent discoveries of biological functions for left-handed Z-conformations have demonstrated important roles in immunity against infectious agents and cancers. More generally, research on Z conformations underscore the impact of alternative DNA and RNA conformations in both normal cellular function and disease. They further emphasize that regulatory information is encoded by structure in addition to sequence.

This joint Special Issue between two flagship MDPI journals—Molecules and the International Journal of Molecular Sciences—intends to summarize the status of Z-DNA and Z-RNA research. With this collection, we aim to help build collaborations across the many disciplines that study these conformations and their implications in biology.

We invite authors to help develop a roadmap to guide future discoveries by submitting a review at the leading edge of their respective fields, to either Molecules or IJMS, according to their preference as well as journal aims and scopes.

More on recent Z-related research at the virtual ABZ2022 meeting on September 7, 2022; free registration at abz.bio.

Dr. Alan Herbert
Dr. Maria S. Poptsova
Dr. Beat Vögeli
Dr. Quentin Vicens
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • ADAR
  • autoimmune disease
  • cancer
  • gene regulation
  • Z-DNA
  • Z-RNA
  • Zα
  • ZBP1
  • Flipons
  • viral immunity
  • base modification
  • topology
  • DNA repeats

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Related Special Issue

Published Papers (6 papers)

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Editorial

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5 pages, 220 KiB  
Editorial
Special Issue: A, B and Z: The Structure, Function and Genetics of Z-DNA and Z-RNA
by Alan Herbert, Sergey Karapetyan, Maria Poptsova, Karen M. Vasquez, Quentin Vicens and Beat Vögeli
Int. J. Mol. Sci. 2021, 22(14), 7686; https://doi.org/10.3390/ijms22147686 - 19 Jul 2021
Cited by 4 | Viewed by 3579
Abstract
It is now difficult to believe that a biological function for the left-handed Z-DNA and Z-RNA conformations was once controversial. The papers in this Special Issue, “Z-DNA and Z-RNA: from Physical Structure to Biological Function”, are based on presentations at the ABZ2021 meeting [...] Read more.
It is now difficult to believe that a biological function for the left-handed Z-DNA and Z-RNA conformations was once controversial. The papers in this Special Issue, “Z-DNA and Z-RNA: from Physical Structure to Biological Function”, are based on presentations at the ABZ2021 meeting that was held virtually on 19 May 2021 and provide evidence for several biological functions of these structures. The first of its kind, this international conference gathered over 200 scientists from many disciplines to specifically address progress in research involving Z-DNA and Z-RNA. These high-energy left-handed conformers of B-DNA and A-RNA are associated with biological functions and disease outcomes, as evidenced from both mouse and human genetic studies. These alternative structures, referred to as “flipons”, form under physiological conditions, regulate type I interferon responses and induce necroptosis during viral infection. They can also stimulate genetic instability, resulting in adaptive evolution and diseases such as cancer. The meeting featured cutting-edge science that was, for the most part, unpublished. We plan for the ABZ meeting to reconvene in 2022. Full article
(This article belongs to the Special Issue Z-DNA and Z-RNA: From Physical Structure to Biological Function)

Research

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29 pages, 9850 KiB  
Article
Conserved microRNAs and Flipons Shape Gene Expression during Development by Altering Promoter Conformations
by Alan Herbert, Fedor Pavlov, Dmitrii Konovalov and Maria Poptsova
Int. J. Mol. Sci. 2023, 24(5), 4884; https://doi.org/10.3390/ijms24054884 - 3 Mar 2023
Cited by 7 | Viewed by 2754
Abstract
The classical view of gene regulation draws from prokaryotic models, where responses to environmental changes involve operons regulated by sequence-specific protein interactions with DNA, although it is now known that operons are also modulated by small RNAs. In eukaryotes, pathways based on microRNAs [...] Read more.
The classical view of gene regulation draws from prokaryotic models, where responses to environmental changes involve operons regulated by sequence-specific protein interactions with DNA, although it is now known that operons are also modulated by small RNAs. In eukaryotes, pathways based on microRNAs (miR) regulate the readout of genomic information from transcripts, while alternative nucleic acid structures encoded by flipons influence the readout of genetic programs from DNA. Here, we provide evidence that miR- and flipon-based mechanisms are deeply connected. We analyze the connection between flipon conformation and the 211 highly conserved human miR that are shared with other placental and other bilateral species. The direct interaction between conserved miR (c-miR) and flipons is supported by sequence alignments and the engagement of argonaute proteins by experimentally validated flipons as well as their enrichment in promoters of coding transcripts important in multicellular development, cell surface glycosylation and glutamatergic synapse specification with significant enrichments at false discovery rates as low as 10−116. We also identify a second subset of c-miR that targets flipons essential for retrotransposon replication, exploiting that vulnerability to limit their spread. We propose that miR can act in a combinatorial manner to regulate the readout of genetic information by specifying when and where flipons form non-B DNA (NoB) conformations, providing the interactions of the conserved hsa-miR-324-3p with RELA and the conserved hsa-miR-744 with ARHGAP5 genes as examples. Full article
(This article belongs to the Special Issue Z-DNA and Z-RNA: From Physical Structure to Biological Function)
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14 pages, 1339 KiB  
Article
Z-DNA as a Tool for Nuclease-Free DNA Methyltransferase Assay
by Sook Ho Kim, Hae Jun Jung and Seok-Cheol Hong
Int. J. Mol. Sci. 2021, 22(21), 11990; https://doi.org/10.3390/ijms222111990 - 5 Nov 2021
Cited by 4 | Viewed by 2547
Abstract
Methylcytosines in mammalian genomes are the main epigenetic molecular codes that switch off the repertoire of genes in cell-type and cell-stage dependent manners. DNA methyltransferases (DMT) are dedicated to managing the status of cytosine methylation. DNA methylation is not only critical in normal [...] Read more.
Methylcytosines in mammalian genomes are the main epigenetic molecular codes that switch off the repertoire of genes in cell-type and cell-stage dependent manners. DNA methyltransferases (DMT) are dedicated to managing the status of cytosine methylation. DNA methylation is not only critical in normal development, but it is also implicated in cancers, degeneration, and senescence. Thus, the chemicals to control DMT have been suggested as anticancer drugs by reprogramming the gene expression profile in malignant cells. Here, we report a new optical technique to characterize the activity of DMT and the effect of inhibitors, utilizing the methylation-sensitive B-Z transition of DNA without bisulfite conversion, methylation-sensing proteins, and polymerase chain reaction amplification. With the high sensitivity of single-molecule FRET, this method detects the event of DNA methylation in a single DNA molecule and circumvents the need for amplification steps, permitting direct interpretation. This method also responds to hemi-methylated DNA. Dispensing with methylation-sensitive nucleases, this method preserves the molecular integrity and methylation state of target molecules. Sparing methylation-sensing nucleases and antibodies helps to avoid errors introduced by the antibody’s incomplete specificity or variable activity of nucleases. With this new method, we demonstrated the inhibitory effect of several natural bio-active compounds on DMT. All taken together, our method offers quantitative assays for DMT and DMT-related anticancer drugs. Full article
(This article belongs to the Special Issue Z-DNA and Z-RNA: From Physical Structure to Biological Function)
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15 pages, 1836 KiB  
Article
The Binding of Monoclonal and Polyclonal Anti-Z-DNA Antibodies to DNA of Various Species Origin
by Diane M. Spencer, Angel Garza Reyna and David S. Pisetsky
Int. J. Mol. Sci. 2021, 22(16), 8931; https://doi.org/10.3390/ijms22168931 - 19 Aug 2021
Cited by 9 | Viewed by 3074
Abstract
DNA is a polymeric macromolecule that can display a variety of backbone conformations. While the classical B-DNA is a right-handed double helix, Z-DNA is a left-handed helix with a zig-zag orientation. The Z conformation depends upon the base sequence, base modification and supercoiling [...] Read more.
DNA is a polymeric macromolecule that can display a variety of backbone conformations. While the classical B-DNA is a right-handed double helix, Z-DNA is a left-handed helix with a zig-zag orientation. The Z conformation depends upon the base sequence, base modification and supercoiling and is considered to be transient. To determine whether the presence of Z-DNA can be detected immunochemically, the binding of monoclonal and polyclonal anti-Z-DNA antibodies to a panel of natural DNA antigens was assessed by an ELISA using brominated poly(dG-dC) as a control for Z-DNA. As these studies showed, among natural DNA tested (Micrococcus luteus, calf thymus, Escherichiacoli, salmon sperm, lambda phage), micrococcal (MC) DNA showed the highest binding with both anti-Z-DNA preparations, and E. coli DNA showed binding with the monoclonal anti-DNA preparation. The specificity for Z-DNA conformation in MC DNA was demonstrated by an inhibition binding assay. An algorithm to identify propensity to form Z-DNA indicated that DNA from Mycobacterium tuberculosis could form Z-DNA, a prediction confirmed by immunoassay. Together, these findings indicate that anti-Z-DNA antibodies can serve as probes for the presence of Z-DNA in DNA of various species origin and that the content of Z-DNA varies significantly among DNA sources. Full article
(This article belongs to the Special Issue Z-DNA and Z-RNA: From Physical Structure to Biological Function)
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Review

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25 pages, 4318 KiB  
Review
Mono a Mano: ZBP1’s Love–Hate Relationship with the Kissing Virus
by Alan Herbert, Aleksandr Fedorov and Maria Poptsova
Int. J. Mol. Sci. 2022, 23(6), 3079; https://doi.org/10.3390/ijms23063079 - 12 Mar 2022
Cited by 6 | Viewed by 4921
Abstract
Z-DNA binding protein (ZBP1) very much represents the nuclear option. By initiating inflammatory cell death (ICD), ZBP1 activates host defenses to destroy infectious threats. ZBP1 is also able to induce noninflammatory regulated cell death via apoptosis (RCD). ZBP1 senses the presence of left-handed [...] Read more.
Z-DNA binding protein (ZBP1) very much represents the nuclear option. By initiating inflammatory cell death (ICD), ZBP1 activates host defenses to destroy infectious threats. ZBP1 is also able to induce noninflammatory regulated cell death via apoptosis (RCD). ZBP1 senses the presence of left-handed Z-DNA and Z-RNA (ZNA), including that formed by expression of endogenous retroelements. Viruses such as the Epstein–Barr “kissing virus” inhibit ICD, RCD and other cell death signaling pathways to produce persistent infection. EBV undergoes lytic replication in plasma cells, which maintain detectable levels of basal ZBP1 expression, leading us to suggest a new role for ZBP1 in maintaining EBV latency, one of benefit for both host and virus. We provide an overview of the pathways that are involved in establishing latent infection, including those regulated by MYC and NF-κB. We describe and provide a synthesis of the evidence supporting a role for ZNA in these pathways, highlighting the positive and negative selection of ZNA forming sequences in the EBV genome that underscores the coadaptation of host and virus. Instead of a fight to the death, a state of détente now exists where persistent infection by the virus is tolerated by the host, while disease outcomes such as death, autoimmunity and cancer are minimized. Based on these new insights, we propose actionable therapeutic approaches to unhost EBV. Full article
(This article belongs to the Special Issue Z-DNA and Z-RNA: From Physical Structure to Biological Function)
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14 pages, 2156 KiB  
Review
Deciphering the Biological Significance of ADAR1–Z-RNA Interactions
by Taisuke Nakahama and Yukio Kawahara
Int. J. Mol. Sci. 2021, 22(21), 11435; https://doi.org/10.3390/ijms222111435 - 23 Oct 2021
Cited by 18 | Viewed by 4624
Abstract
Adenosine deaminase acting on RNA 1 (ADAR1) is an enzyme responsible for double-stranded RNA (dsRNA)-specific adenosine-to-inosine RNA editing, which is estimated to occur at over 100 million sites in humans. ADAR1 is composed of two isoforms transcribed from different promoters: p150 and N-terminal [...] Read more.
Adenosine deaminase acting on RNA 1 (ADAR1) is an enzyme responsible for double-stranded RNA (dsRNA)-specific adenosine-to-inosine RNA editing, which is estimated to occur at over 100 million sites in humans. ADAR1 is composed of two isoforms transcribed from different promoters: p150 and N-terminal truncated p110. Deletion of ADAR1 p150 in mice activates melanoma differentiation-associated protein 5 (MDA5)-sensing pathway, which recognizes endogenous unedited RNA as non-self. In contrast, we have recently demonstrated that ADAR1 p110-mediated RNA editing does not contribute to this function, implying that a unique Z-DNA/RNA-binding domain α (Zα) in the N terminus of ADAR1 p150 provides specific RNA editing, which is critical for preventing MDA5 activation. In addition, a mutation in the Zα domain is identified in patients with Aicardi–Goutières syndrome (AGS), an inherited encephalopathy characterized by overproduction of type I interferon. Accordingly, we and other groups have recently demonstrated that Adar1 Zα-mutated mice show MDA5-dependent type I interferon responses. Furthermore, one such mutant mouse carrying a W197A point mutation in the Zα domain, which inhibits Z-RNA binding, manifests AGS-like encephalopathy. These findings collectively suggest that Z-RNA binding by ADAR1 p150 is essential for proper RNA editing at certain sites, preventing aberrant MDA5 activation. Full article
(This article belongs to the Special Issue Z-DNA and Z-RNA: From Physical Structure to Biological Function)
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