Zα and Zβ Localize ADAR1 to Flipons That Modulate Innate Immunity, Alternative Splicing, and Nonsynonymous RNA Editing DOI Open Access
Alan Herbert, Oleksandr Cherednichenko, Terry P. Lybrand

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(6), P. 2422 - 2422

Published: March 7, 2025

The double-stranded RNA editing enzyme ADAR1 connects two forms of genetic programming, one based on codons and the other flipons. recodes in pre-mRNA by deaminating adenosine to form inosine, which is translated as guanosine. also plays essential roles immune defense against viruses cancers recognizing left-handed Z-DNA Z-RNA (collectively called ZNA). Here, we review various aspects biology, starting with progressing has major isoforms, p110 protein lacking p150 Zα domain that binds ZNAs high affinity. isoform induced interferon targets ALU inverted repeats, a class endogenous retroelement promotes their transcription retrotransposition incorporating Z-flipons encode G-flipons G-quadruplexes (GQ). Both include Zβ related but does not bind ZNAs. Here report strong evidence GQ are formed co-transcriptionally repeats within R-loops. By binding GQ, suppresses ALU-mediated alternative splicing, generates most reported nonsynonymous edits R-loop resolution. recognition nucleic acid conformations programming flipons encoding information codons. findings suggest into editmers might improve therapeutic efficacy ADAR1.

Language: Английский

Redox regulation of m6A methyltransferase METTL3 in β-cells controls the innate immune response in type 1 diabetes DOI
Dario F. De Jesus, Zijie Zhang, Natalie K. Brown

et al.

Nature Cell Biology, Journal Year: 2024, Volume and Issue: 26(3), P. 421 - 437

Published: Feb. 26, 2024

Language: Английский

Citations

18
The competitive landscape of the dsRNA world DOI Creative Commons
Kyle A. Cottrell, Ryan J. Andrews, Brenda Bass

et al.

Molecular Cell, Journal Year: 2023, Volume and Issue: 84(1), P. 107 - 119

Published: Dec. 19, 2023

Language: Английский

Citations

33
Induction of Viral Mimicry Upon Loss of DHX9 and ADAR1 in Breast Cancer Cells DOI Creative Commons
Kyle A. Cottrell, Sua Ryu, Jackson R. Pierce

et al.

Cancer Research Communications, Journal Year: 2024, Volume and Issue: 4(4), P. 986 - 1003

Published: March 26, 2024

Abstract Detection of viral double-stranded RNA (dsRNA) is an important component innate immunity. However, many endogenous RNAs containing regions can be misrecognized and activate The IFN-inducible ADAR1-p150 suppresses dsRNA sensing, essential function for adenosine deaminase acting on 1 (ADAR1) in cancers, including breast. Although has been well established this role, the functions constitutively expressed ADAR1-p110 isoform are less understood. We used proximity labeling to identify putative ADAR1-p110–interacting proteins breast cancer cell lines. Of identified, helicase DHX9 was particular interest. Knockdown ADAR1-dependent lines caused death activation sensor PKR. In ADAR1-independent lines, combined knockdown ADAR1, but neither alone, multiple sensing pathways leading a mimicry phenotype. Together, these results reveal role suppressing by pathways. Significance: These findings implicate as suppressor sensing. some loss alone sufficient cause pathways, while other redundantly with ADAR1 suppress pathway activation.

Language: Английский

Citations

15
RNA editing enzymes: structure, biological functions and applications DOI Creative Commons
Dejiu Zhang,

Lei Zhu,

Yanyan Gao

et al.

Cell & Bioscience, Journal Year: 2024, Volume and Issue: 14(1)

Published: March 16, 2024

Abstract With the advancement of sequencing technologies and bioinformatics, over than 170 different RNA modifications have been identified. However, only a few these can lead to base pair changes, which are called editing. editing is ubiquitous modification in mammalian transcriptomes an important co/posttranscriptional that plays crucial role various cellular processes. There two main types events: adenosine inosine (A-to-I) editing, catalyzed by ADARs on double-stranded or ADATs tRNA, cytosine uridine (C-to-U) APOBECs. This article provides overview structure, function, applications enzymes. We discuss structural characteristics three enzyme families their catalytic mechanisms also explain biological particularly innate immunity, cancer biogenesis, antiviral activity. Additionally, this describes tools for manipulating correct disease-causing mutations, as well potential enzymes field biotechnology therapy.

Language: Английский

Citations

12
ADAR1: from basic mechanisms to inhibitors DOI Creative Commons
Jan Rehwinkel, Parinaz Mehdipour

Trends in Cell Biology, Journal Year: 2024, Volume and Issue: unknown

Published: July 1, 2024

Adenosine deaminase acting on RNA 1 (ADAR1) converts adenosine to inosine in double-stranded (dsRNA) molecules, a process known as A-to-I editing. ADAR1 deficiency humans and mice results profound inflammatory diseases characterised by the spontaneous induction of innate immunity. In cells lacking ADAR1, unedited RNAs activate sensors. These include melanoma differentiation-associated gene 5 (MDA5) that induces expression cytokines, particularly type I interferons (IFNs), protein kinase R (PKR), oligoadenylate synthase (OAS), Z-DNA/RNA binding (ZBP1). Immunogenic 'defused' may transcripts from repetitive elements other long duplex RNAs. Here, we review these recent fundamental discoveries discuss implications for human diseases. Some tumours depend escape immune surveillance, opening possibility unleashing anticancer therapies with inhibitors.

Language: Английский

Citations

11
Retroelement decay by the exonuclease XRN1 is a viral mimicry dependency in cancer DOI Creative Commons
Amir Hosseini, Håvard T. Lindholm, Raymond Chen

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(2), P. 113684 - 113684

Published: Jan. 22, 2024

Viral mimicry describes the immune response induced by endogenous stimuli such as double-stranded RNA (dsRNA) from retroelements. Activation of viral has potential to kill cancer cells or augment anti-tumor responses. Here, we systematically identify mechanisms adaptation associated with cell dependencies. Among top hits is decay protein XRN1 an essential gene for survival a subset lines. dependency mediated mitochondrial antiviral signaling and kinase R activation higher levels cytosolic dsRNA, Alus capable forming interferon-stimulated expression, indicating that die due induction mimicry. Furthermore, dsRNA-inducing drugs 5-aza-2'-deoxycytidine palbociclib can generate synthetic on in initially resistant knockout. These results indicate promising target future therapeutics.

Language: Английский

Citations

10
An ADAR1 dsRBD3-PKR kinase domain interaction on dsRNA inhibits PKR activation DOI Creative Commons
Ketty Sinigaglia, Anna Cherian,

Qiupei Du

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(8), P. 114618 - 114618

Published: Aug. 1, 2024

Adar null mutant mouse embryos die with aberrant double-stranded RNA (dsRNA)-driven interferon induction, and Mavs double mutants, in which induction is prevented, soon after birth. Protein kinase R (Pkr) aberrantly activated pup intestines before death, intestinal crypt cells die, villi are lost. Eifak2 triple mice rescue all defects have long-term survival. Adenosine deaminase acting on 1 (ADAR1) PKR co-immunoprecipitate from cells, suggesting inhibition by direct interaction. AlphaFold studies an inhibitory dsRNA binding domain (dsRBD)-kinase interaction ADAR1 dsRBD3-PKR provide a testable model of the inhibition. Wild-type or editing-inactive human expressed A549 inhibits activation endogenous PKR. required for, but not sufficient Mutating contact prevents co-immunoprecipitation, activity, co-localization cells.

Language: Английский

Citations

10
A Wonderful Journey: The Diverse Roles of Adenosine Deaminase Action on RNA 1 (ADAR1) in Central Nervous System Diseases DOI Creative Commons
Lin Cheng, Ziying Liu,

Chunxiao Shen

et al.

CNS Neuroscience & Therapeutics, Journal Year: 2025, Volume and Issue: 31(1)

Published: Jan. 1, 2025

ABSTRACT Background Adenosine deaminase action on RNA 1 (ADAR1) can convert the adenosine in double‐stranded (dsRNA) molecules into inosine a process known as A‐to‐I editing. ADAR1 regulates gene expression output by interacting with and other proteins; plays important roles development, including growth; is linked to innate immunity, tumors, central nervous system (CNS) diseases. Results In recent years, role of tumors has been widely discussed, but its CNS diseases not reviewed. It worth noting that studies have shown great potential treatment neurodegenerative diseases, mechanisms are still unclear. Therefore, it necessary elaborate Conclusions Here, we focus effects such Aicardi–AicardiGoutières syndrome, Alzheimer's disease, Parkinson's glioblastoma, epilepsy, amyotrophic lateral sclerosis, autism. We also evaluate impact ADAR1‐based strategies these particular development new technologies microRNAs, nanotechnology, editing, stem cell therapy. hope provide directions insights for future editing technology brain science

Language: Английский

Citations

1
In search of critical dsRNA targets of ADAR1 DOI Creative Commons
Erez Y. Levanon, Roni Cohen‐Fultheim, Eli Eisenberg

et al.

Trends in Genetics, Journal Year: 2023, Volume and Issue: 40(3), P. 250 - 259

Published: Dec. 29, 2023

Recent studies have underscored the pivotal role of adenosine-to-inosine RNA editing, catalyzed by ADAR1, in suppressing innate immune interferon responses triggered cellular double-stranded (dsRNA). However, specific ADAR1 editing targets crucial for this regulatory function remain elusive. We review analyses transcriptome-wide patterns and their evolutionary dynamics, which offer valuable insights into unresolved query. The growing appreciation significance immunogenic dsRNAs inflammatory autoimmune diseases cancer calls a more comprehensive understanding dsRNA immunogenicity, may promote our these open doors to therapeutic avenues.

Language: Английский

Citations

22
Multifaceted roles of RNA editing enzyme ADAR1 in innate immunity DOI Open Access
Inga Jarmoskaite, Jin Billy Li

RNA, Journal Year: 2024, Volume and Issue: 30(5), P. 500 - 511

Published: March 26, 2024

Innate immunity must be tightly regulated to enable sensitive pathogen detection while averting autoimmunity triggered by pathogen-like host molecules. A hallmark of viral infection, double-stranded RNAs (dsRNAs) are also abundantly encoded in mammalian genomes, necessitating surveillance mechanisms distinguish “self” from “nonself.” ADAR1, an RNA editing enzyme, has emerged as essential safeguard against dsRNA-induced autoimmunity. By converting adenosines inosines (A-to-I) long dsRNAs, ADAR1 covalently marks endogenous thereby blocking the activation cytoplasmic dsRNA sensor MDA5. Moreover, beyond its function, binding impedes innate immune sensors PKR and ZBP1. Recent landmark studies underscore utility silencing for cancer immunotherapy, exploiting ADAR1-dependence developed certain tumors unleash antitumor response. In this perspective, we summarize genetic mechanistic evidence ADAR1's multipronged role suppressing dsRNA-mediated explore evolving roles immuno-oncology target.

Language: Английский

Citations

8