The ancient Z-DNA and Z-RNA specific Zα fold has evolved modern roles in immunity and transcription through the natural selection of flipons

Royal Society Open Science, Journal Year: 2024, Volume and Issue: 11(6)

Published: June 1, 2024

The Zα fold specifically binds to both Z-DNA and Z-RNA, left-handed nucleic acid structures that form under physiological conditions are encoded by flipons. I trace the back unicellular organisms representing all three domains of life realm giant nucleocytoplasmic DNA viruses (NCVs). canonical is present in earliest known holozoan symbiont Capsaspora owczarzaki persists vertebrates some invertebrates, but not plants or fungi. In metazoans, starting with porifera, incorporated into double-stranded RNA editing enzyme ADAR reflects an early relationship NCV. vertebrates, also ZBP1 PKZ proteins recognize host-derived Z-RNAs defend against modern-day viruses. A related fold, likely bind Z-DNA, thought modulate gene expression, including a subset prokaryote arsR p15 (PC4) family algae. Other variants probably play more general role reinitiation transcription include archaeal human factor E polymerase 3 subunit C proteins. roles immunity underlie natural selection

Language: Английский

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Z-DNA formation in promoters conserved between human and mouse are associated with increased transcription reinitiation rates

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Aug. 1, 2024

A long-standing question concerns the role of Z-DNA in transcription. Here we use a deep learning approach DeepZ that predicts Z-flipons based on DNA sequence, structural properties nucleotides and omics data. We examined are conserved between human mouse genomes after generating whole-genome Z-flipon maps then validated them by orthogonal approaches high resolution chemical mapping transformer algorithm Z-DNABERT. For mouse, revealed similar pattern transcription factors, chromatin remodelers, histone marks associated with Z-flipons. found significant enrichment alternative bidirectional promoters neurogenesis genes. show increased experimentally determined reinitiation rates compared to without Z-flipons, but affecting elongation or pausing. Our findings support model where engage Transcription Factor E impact phenotype enabling reset preinitiation complexes when active, suppression gene expression engaged repressive complexes.

Language: Английский

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Flipons and small RNAs accentuate the asymmetries of pervasive transcription by the reset and sequence-specific microcoding of promoter conformation

Journal of Biological Chemistry, Journal Year: 2023, Volume and Issue: 299(9), P. 105140 - 105140

Published: Aug. 6, 2023

The role of alternate DNA conformations such as Z-DNA in the regulation transcription is currently underappreciated. These structures are encoded by sequences called flipons, many which enriched promoter and enhancer regions. Through a change their conformation, flipons provide tunable mechanism to mechanically reset promoters for next round transcription. They act actuators that capture release energy ensure turnover proteins at optimized cell state. Likewise, single-stranded formed cycle facilitates docking RNAs able microcode canalize pervasive commonly observed metazoan genomes. strand-specific nature interaction between RNA likely accounts known asymmetry epigenetic marks present on histone tetramers pair form nucleosomes. these supercoil-dependent processes choice transcriptional interference reviewed. evolutionary implications examined: resilience canalization flipon-dependent gene contrasted with rapid adaptation enabled spread flipon repeats throughout genome. Overall, current findings underscore important modulating readout genetic information how little we know about biology.

Language: Английский

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Conserved microRNAs and Flipons Shape Gene Expression during Development by Altering Promoter Conformations

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(5), P. 4884 - 4884

Published: March 3, 2023

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 are also modulated small RNAs. In eukaryotes, pathways based on microRNAs (miR) regulate the readout genomic information transcripts, while alternative nucleic acid structures encoded flipons influence genetic programs DNA. Here, we provide evidence miR- and flipon-based mechanisms deeply connected. We analyze connection between flipon conformation 211 highly conserved human miR shared other placental bilateral species. direct interaction (c-miR) supported sequence alignments engagement argonaute proteins experimentally validated as well their enrichment in promoters coding transcripts important multicellular development, cell surface glycosylation glutamatergic synapse specification significant enrichments at false discovery rates low 10-116. identify a second subset c-miR targets essential for retrotransposon replication, exploiting vulnerability limit spread. propose can act combinatorial manner specifying when form non-B DNA (NoB) conformations, providing hsa-miR-324-3p RELA hsa-miR-744 ARHGAP5 genes examples.

Language: Английский

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Z-flipon variants reveal the many roles of Z-DNA and Z-RNA in health and disease

Life Science Alliance, Journal Year: 2023, Volume and Issue: 6(7), P. e202301962 - e202301962

Published: May 10, 2023

Identifying roles for Z-DNA remains challenging given their dynamic nature. Here, we perform genome-wide interrogation with the DNABERT transformer algorithm trained on experimentally identified forming sequences (Z-flipons). The yields large performance enhancements (F1 = 0.83) over existing approaches and implements computational mutagenesis to assess effects of base substitution formation. We show Z-flipons are enriched in promoters telomeres, overlapping quantitative trait loci RNA expression, editing, splicing, disease-associated variants. cross-validate across a number orthogonal databases define BZ junction motifs. Surprisingly, many delineate likely mediated through Z-RNA A shared motif is SCARF2, SMAD1, CACNA1 transcripts, whereas other motifs present noncoding RNAs. provide evidence fold that promotes adaptive immunity alternative splicing KRAB domain zinc finger proteins. An analysis OMIM presumptive gnomAD loss-of-function datasets reveals an overlap disease-causing variants 8.6% 2.9% Mendelian disease genes, respectively, greatly extending range phenotypes mapped Z-flipons.

Language: Английский

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A Compendium of G-flipon Biological Functions that have Experimental Validation

Published: Aug. 23, 2024

As with all new fields of discovery, work on the biological role G-quadruplexes (GQ) has produced a number results that at first glance are quite baffling, sometimes because they do not fit well together, but mostly different from commonly held expectations. Like other classes flipons, those form have repeat sequence motif enables fold. The canonical DNA (G3N1-7)3G3, where N is any nucleotide and G guanine, feature under active selection in avian mammalian genomes. involvement G-flipons genome maintenance traces back to invertebrate C. elegans ancient repair pathways. A for GQ transcription supported by observation yeast Rap1 protein binds both B-DNA, sequence-specific manner, GQ, structure-specific through same helix. Other factors (TF) also engage conformations. RNAs can modulate formation manner cellular machinery as localized TF, linking RNA world modern world. coevolution proteins studies early embryonic development, transient potentially coordinates epigenetic specification cell fate.

Language: Английский

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Flipons enable genomes to learn by intermediating the exchange of energy for information

Journal of The Royal Society Interface, Journal Year: 2025, Volume and Issue: 22(224)

Published: March 1, 2025

Recent findings have confirmed the long-held belief that alternative DNA conformations encoded by genetic elements called flipons important biological roles. Many of these structures are formed sequences originally spread throughout human genome endogenous retroelements (ERE) captured 50% territory before being disarmed. Only 2.6% remaining codes for proteins. Other organisms instead streamlined their genomes eliminating invasive and other repeat elements. The question arises, why retain any ERE at all? A new synthesis suggests enable to learn programme context-specific readout information altering transcripts produced. exchange energy is mediated through changes in topology. Here I provide a formulation how describe underlying p-bit algorithm which tuned. framework strategies therapeutic reprogramming cells.

Language: Английский

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A Compendium of G-Flipon Biological Functions That Have Experimental Validation

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(19), P. 10299 - 10299

Published: Sept. 25, 2024

As with all new fields of discovery, work on the biological role G-quadruplexes (GQs) has produced a number results that at first glance are quite baffling, sometimes because they do not fit well together, but mostly different from commonly held expectations. Like other classes flipons, those form have repeat sequence motif enables fold. The canonical DNA (G3N1–7)3G3, where N is any nucleotide and G guanine, feature under active selection in avian mammalian genomes. involvement G-flipons genome maintenance traces back to invertebrate Caenorhabditis elegans ancient repair pathways. GQs transcription supported by observation yeast Rap1 protein binds both B-DNA, sequence-specific manner, GQs, structure-specific through same helix. Other factors (TFs) also engage conformations actuate cellular transactions. Noncoding RNAs can modulate GQ formation manner machinery as localized TFs, linking RNA world modern world. coevolution noncoding proteins studies early embryonic development, transient coordinates epigenetic specification cell fate.

Language: Английский

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Z-DNA and Z-RNA: Methods—Past and Future

Methods in molecular biology, Journal Year: 2023, Volume and Issue: unknown, P. 295 - 329

Published: Jan. 1, 2023

Language: Английский

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Extensive Bioinformatics Analyses Reveal a Phylogenetically Conserved Winged Helix (WH) Domain (Zτ) of Topoisomerase IIα, Elucidating Its Very High Affinity for Left-Handed Z-DNA and Suggesting Novel Putative Functions

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(13), P. 10740 - 10740

Published: June 27, 2023

The dynamic processes operating on genomic DNA, such as gene expression and cellular division, lead inexorably to topological challenges in the form of entanglements, catenanes, knots, “bubbles”, R-loops, other outcomes supercoiling helical disruption. resolution toxic stress is function attributed DNA topoisomerases. A prominent example negative (nsc) trailing processive enzymes RNA polymerases. multiple equilibrium states that nscDNA can adopt by redistribution twist writhe include left-handed double-helical conformation known Z-DNA. Thirty years ago, one our labs isolated a protein from Drosophila cells embryos with 100-fold greater affinity for Z-DNA than B-DNA, identified it topoisomerase II (gene Top2, orthologous human UniProt proteins TOP2A TOP2B). GTP increased selectivity even further also led inhibition isomerase enzymatic activity. An allosteric mechanism was proposed, which topoII acts Z-DNA-binding (ZBP) stabilize given (sub)domains associated multiprotein complexes. We have now explored this possibility comprehensive bioinformatic analyses available sequences representing organisms covering whole tree life. Multiple alignment these revealed an extremely high level evolutionary conservation, including winged-helix segment, here denoted Zτ, constituting putative structural homolog Zα, canonical Z-DNA/Z-RNA binding domain previously interferon-inducible Adenosine-to-Inosine-editing deaminase, ADAR1p150. In contrast separate segment responsible catalysis, Zτ encompasses active site tyrosine topoII; GTP-binding GxxG sequence motif are close proximity. Quantitative Zτ-Zα similarity comparisons molecular docking interaction scoring supported “B-Z-topoII hypothesis” has expanded incorporating recognition segments (“Z-flipons”) inherent essential element. propose two domains homodimer exhibit single-turnover “conformase” activity G(ate) B-DNA (“Z-flipins”), inducing their transition Z-conformation. Inasmuch topoII-Z-DNA complexes inactive, we infer they fulfill important roles key mitosis. Topoisomerases preeminent targets anti-cancer drug discovery, anticipate detailed elucidation structural–functional interactions will facilitate design novel, more potent selective chemotherapeutic agents.

Language: Английский

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