RNA Structure: Past, Future, and Gene Therapy Applications DOI Open Access
William A. Haseltine,

Kim Hazel,

Roberto Patarca

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 26(1), P. 110 - 110

Published: Dec. 26, 2024

First believed to be a simple intermediary between the information encoded in deoxyribonucleic acid and that functionally displayed proteins, ribonucleic (RNA) is now known have many functions through its abundance intricate, ubiquitous, diverse, dynamic structure. About 70–90% of human genome transcribed into protein-coding noncoding RNAs as main determinants along with regulatory sequences cellular populational biological diversity. From nucleotide sequence or primary structure, Watson–Crick pairing self-folding secondary compaction via longer distance non-Watson–Crick interactions tertiary RNA other biopolymers quaternary metabolites biomolecules quinary structure plays critical role RNA’s lifecycle from transcription decay processes. In contrast success 3-dimensional protein prediction using AlphaFold, beyond structures remains challenging. However, approaches involving machine learning artificial intelligence, sequencing modifications, structural analyses at single-cell intact tissue levels, among others, provide an optimistic outlook for continued development refinement RNA-based applications. Here, we highlight those gene therapy.

Language: Английский

Chemistry, structure and function of approved oligonucleotide therapeutics DOI Creative Commons
Martin Egli, Muthiah Manoharan

Nucleic Acids Research, Journal Year: 2023, Volume and Issue: 51(6), P. 2529 - 2573

Published: March 7, 2023

Eighteen nucleic acid therapeutics have been approved for treatment of various diseases in the last 25 years. Their modes action include antisense oligonucleotides (ASOs), splice-switching (SSOs), RNA interference (RNAi) and an aptamer against a protein. Among targeted by this new class drugs are homozygous familial hypercholesterolemia, spinal muscular atrophy, Duchenne dystrophy, hereditary transthyretin-mediated amyloidosis, chylomicronemia syndrome, acute hepatic porphyria, primary hyperoxaluria. Chemical modification DNA was central to making out oligonucleotides. Oligonucleotide brought market thus far contain just handful first- second-generation modifications, among them 2'-fluoro-RNA, 2'-O-methyl phosphorothioates that were introduced over 50 years ago. Two other privileged chemistries 2'-O-(2-methoxyethyl)-RNA (MOE) phosphorodiamidate morpholinos (PMO). Given their importance imparting with high target affinity, metabolic stability favorable pharmacokinetic -dynamic properties, article provides review these use therapeutics. Breakthroughs lipid formulation GalNAc conjugation modified paved way efficient delivery robust, long-lasting silencing genes. This account state-of-the-art oligo hepatocytes.

Language: Английский

Citations

400
The Z-nucleic acid sensor ZBP1 in health and disease DOI Creative Commons
Jonathan Maelfait, Jan Rehwinkel

The Journal of Experimental Medicine, Journal Year: 2023, Volume and Issue: 220(8)

Published: July 14, 2023

Nucleic acid sensing is a central process in the immune system, with far-reaching roles antiviral defense, autoinflammation, and cancer. Z-DNA binding protein 1 (ZBP1) sensor for double-stranded DNA RNA helices unusual left-handed Z conformation termed Z-RNA. Recent research established ZBP1 as key upstream regulator of cell death proinflammatory signaling. Recognition Z-DNA/RNA by promotes host resistance to viral infection but can also drive detrimental autoinflammation. Additionally, has interesting cancer other disease settings emerging an attractive target therapy.

Language: Английский

Citations

39
Novel insights into double-stranded RNA-mediated immunopathology DOI
Richard de Reuver, Jonathan Maelfait

Nature reviews. Immunology, Journal Year: 2023, Volume and Issue: 24(4), P. 235 - 249

Published: Sept. 26, 2023

Language: Английский

Citations

30
The ancient Z-DNA and Z-RNA specific Zα fold has evolved modern roles in immunity and transcription through the natural selection of flipons DOI Creative Commons
Alan Herbert

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

Citations

11
Systemic lupus erythematosus genetics: insights into pathogenesis and implications for therapy DOI
Yogita Ghodke‐Puranik,

Mikhail Olferiev,

Mary K. Crow

et al.

Nature Reviews Rheumatology, Journal Year: 2024, Volume and Issue: 20(10), P. 635 - 648

Published: Sept. 4, 2024

Language: Английский

Citations

9
Global identification and functional characterization of Z‐DNA in rice DOI Creative Commons
Zexue He,

Yonghang Run,

Yilong Feng

et al.

Plant Biotechnology Journal, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

Summary Z‐DNA is a left‐handed double helix form of DNA that believed to be involved in various transactions. However, comprehensive investigations aimed at global profiling landscapes are still missing both humans and plants. We here report the development two techniques: anti‐Z‐DNA antibody‐based immunoprecipitation followed by sequencing (ZIP‐seq), cleavage under targets tagmentation (CUT&TAG) for characterizing nipponbare rice ( Oryza sativa L., Japonica). found Z‐DNA‐IP + (Z‐DNA recognized antibody) exhibits distinct genomic features as compared − not antibody). The concomitant presence G‐quadruplexes (G4s) i‐motifs (iMs) may promote formation. modifications such DNA‐6mA/‐4acC generally disfavours formation, while like DNA‐5mC (CHH) 8‐oxodG it, highlighting roles base modulating Importantly, located transcription start sites (TSSs) enhances gene expression, whereas genic regions represses underscoring its dual regulating expression genes fundamental biological functions responses salt stress. Furthermore, play role transcriptional initiation termination rather than elongation. Finally, promoters correlated with coevolution overlapping genes, thereby domestication. Consequently, our study represents pivotal point solid foundation reliably launching genome‐wide Z‐DNA, advancing understanding biology plants non‐plant systems.

Language: Английский

Citations

1
A ZBP1 isoform blocks ZBP1-mediated cell death DOI Creative Commons

Zhiyu Cai,

Puqi Wu,

Hao Liang

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(5), P. 114221 - 114221

Published: May 1, 2024

ZBP1 is an interferon (IFN)-induced nucleic acid (NA) sensor that senses unusual Z-form NA (Z-NA) to promote cell death and inflammation. However, the mechanisms dampen activation fine-tune inflammatory responses are unclear. Here, we characterize a short isoform of (referred as ZBP1-S) intrinsic suppressor signaling mediated by full-length ZBP1. Mechanistically, ZBP1-S depresses ZBP1-mediated competitive binding with Z-NA for Zα domains Cells from mice (Ripk1

Language: Английский

Citations

5
Korean Red ginseng enhances ZBP1-mediated cell death to suppress viral protein expression in host defense against Influenza A virus DOI

Ju-Eun Oh,

Hayeon Kim,

Jihye Lee

et al.

The Journal of Microbiology, Journal Year: 2025, Volume and Issue: 63(1), P. e:2409007 - e:2409007

Published: Jan. 24, 2025

Language: Английский

Citations

0
Z-form DNA-RNA hybrid blocks DNA replication DOI Creative Commons
Shiyu Wang, Yan Xu

Nucleic Acids Research, Journal Year: 2025, Volume and Issue: 53(5)

Published: Feb. 27, 2025

We discovered that the Z-form DNA-RNA hybrid stabilized by methylated CpG repeats impacts on initiation and elongation of Okazaki fragments, contributing to blocking DNA replication at first time. further present structure using NMR spectroscopy dynamic computation, revealing molecular mechanism inhibition, indicating a distinctive zig-zag strand pattern with smaller helical diameter (15 Å) very narrow minor groove (8.3 plays key role in repression toward replication.

Language: Английский

Citations

0
Ischemia-reperfusion injury induces ZBP1-dependent PANoptosis in endothelial cells DOI
Yue Cui,

Lin Huang,

Jiaxing Ma

et al.

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Journal Year: 2025, Volume and Issue: unknown, P. 167782 - 167782

Published: March 1, 2025

Language: Английский

Citations

0