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

RNA editing and immune control: from mechanism to therapy DOI Creative Commons

Shi-Bin Hu,

Jin Billy Li

Current Opinion in Genetics & Development, Journal Year: 2024, Volume and Issue: 86, P. 102195 - 102195

Published: April 21, 2024

Language: Английский

Citations

8
Aberrant RNA sensing in regulatory T cells causes systemic autoimmunity DOI Creative Commons
Domnica Luca, Sumin Lee, Keiji Hirota

et al.

Science Advances, Journal Year: 2024, Volume and Issue: 10(9)

Published: March 1, 2024

Chronic and aberrant nucleic acid sensing causes type I IFN–driven autoimmune diseases, designated interferonopathies. We found a significant reduction of regulatory T cells (T regs ) in patients with interferonopathies caused by mutations ADAR1 or IFIH1 (encoding MDA5). analyzed the underlying mechanisms using murine models that reg -specific deletion Adar1 peripheral loss scurfy -like lethal disorders. Similarly, knock-in mice expression an MDA5 gain-of-function mutant apoptosis severe autoimmunity. Moreover, impact deficiency on is multifaceted, involving both PKR sensing. Together, our results highlight dysregulation homeostasis intrinsic RNA as potential determinant for

Language: Английский

Citations

6
Malignant A-to-I RNA editing by ADAR1 drives T cell acute lymphoblastic leukemia relapse via attenuating dsRNA sensing DOI Creative Commons

Maria Rivera,

Haoran Zhang, Jessica Pham

et al.

Cell Reports, Journal Year: 2024, Volume and Issue: 43(2), P. 113704 - 113704

Published: Jan. 23, 2024

Leukemia-initiating cells (LICs) are regarded as the origin of leukemia relapse and therapeutic resistance. Identifying direct stemness determinants that fuel LIC self-renewal is critical for developing targeted approaches. Here, we show RNA-editing enzyme ADAR1 a crucial factor promotes by attenuating aberrant double-stranded RNA (dsRNA) sensing. Elevated adenosine-to-inosine editing common attribute relapsed T cell acute lymphoblastic (T-ALL) regardless molecular subtype. Consequently, knockdown severely inhibits capacity prolongs survival in T-ALL patient-derived xenograft models. Mechanistically, directs hyper-editing immunogenic dsRNA to avoid detection innate immune sensor melanoma differentiation-associated protein 5 (MDA5). Moreover, uncover cell-intrinsic level MDA5 dictates dependency on ADAR1-MDA5 axis T-ALL. Collectively, our results functions limits sensing endogenous dsRNA. Thus, targeting presents an effective strategy eliminating LICs.

Language: Английский

Citations

5
A‐to‐I RNA editing by ADAR and its therapeutic applications: From viral infections to cancer immunotherapy DOI
Rohini Datta, Julia Z. Adamska, Amruta Bhate

et al.

Wiley Interdisciplinary Reviews - RNA, Journal Year: 2023, Volume and Issue: 15(1)

Published: Sept. 17, 2023

Abstract ADAR deaminases catalyze adenosine‐to‐inosine (A‐to‐I) editing on double‐stranded RNA (dsRNA) substrates that regulate an umbrella of biological processes. One the two catalytically active enzymes, ADAR1, plays a major role in innate immune responses by suppression sensing pathways which are orchestrated through ADAR1‐dsRNA‐MDA5 axis. Unedited immunogenic dsRNA potent ligands for cellular sensor MDA5. Upon activation, MDA5 leads to induction interferons and expression hundreds interferon‐stimulated genes with antiviral activity. In this way, ADAR1 acts as gatekeeper pathway striking fine balance between prevention autoimmunity. Reduced is strongly linked development common autoimmune inflammatory diseases. viral infections, exhibits both proviral effects. This modulated editing‐dependent editing‐independent functions, such PKR antagonism. Several A‐to‐I events have been identified viruses, including insidious pathogen, SARS‐CoV‐2 regulates fitness infectivity, could play shaping evolution. Furthermore, attractive target immuno‐oncology therapy. Overexpression increased observed several human cancers. Silencing especially cancers refractory checkpoint inhibitors, promising therapeutic strategy cancer immunotherapy conjunction epigenetic The mechanistic understanding holds great potential applications. article categorized under: Processing > Editing Modification Disease Development

Language: Английский

Citations

12
RNA recognition by PKR during DNA virus infection DOI
Ruilin Zhang, John Karijolich

Journal of Medical Virology, Journal Year: 2024, Volume and Issue: 96(2)

Published: Jan. 29, 2024

Abstract Protein kinase R (PKR) is a double‐stranded RNA (dsRNA) binding protein that plays crucial role in innate immunity during viral infection and can restrict both DNA viruses. The potency of its antiviral function further reflected by the large number viral‐encoded PKR antagonists. However, much about regulation dsRNA accumulation activation remains unknown. Since viruses do not have an genome or replication intermediates like do, PKR‐mediated detection context virus particularly intriguing. Here, we review current state knowledge regarding antagonism with

Language: Английский

Citations

4
Dimerization of ADAR1 modulates site-specificity of RNA editing DOI Creative Commons

Allegra Mboukou,

Vinod Rajendra,

Serafina Messmer

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: Nov. 21, 2024

Abstract Adenosine-to-inosine editing is catalyzed by adenosine deaminases acting on RNA (ADARs) in double-stranded (dsRNA) regions. Although three ADARs exist mammals, ADAR1 responsible for the vast majority of events and acts thousands sites human transcriptome. has been proposed to form a stable homodimer dimerization suggested be important activity. In absence structural basis ADAR1, without way prevent dimer formation, effect enzyme activity or site specificity remained elusive. Here, we report analysis third RNA-binding domain (dsRBD3), which reveals formation through large inter-domain interface. Exploiting these insights, engineered an interface-mutant disrupting ADAR1-dsRBD3 dimerization. Notably, disruption did not abrogate but intricately affected efficiency at selected sites. This suggests complex role selection ADARs, makes potential target modulating

Language: Английский

Citations

4
RNA sensing at the crossroads of autoimmunity and autoinflammation DOI Open Access
Sandra G. Williams, Soyeong Sim, Sandra L. Wolin

et al.

RNA, Journal Year: 2025, Volume and Issue: unknown, P. rna.080304.124 - rna.080304.124

Published: Jan. 8, 2025

Immune-mediated diseases are common in humans. The immune system is a complex host defense that evolved to protect us from pathogens, but also plays an important role homeostatic processes, removing dead or senescent cells, and participating tumor surveillance. human has two arms: the older innate system, newer adaptive system. Sensing of foreign RNA critical system’s ability recognize especially viral infections. However, sensors strongly implicated autoimmune autoinflammatory diseases, highlighting importance balancing pathogen recognition with tolerance RNAs can resemble their counterparts. We describe how bind ligands, this binding coupled upregulation Type I interferon-stimulated genes, ways which mutations genes play roles homeostasis have been linked diseases.

Language: Английский

Citations

0
Biochemical Profiling and Structural Basis of ADAR1-Mediated RNA Editing DOI Creative Commons
Xiangyu Deng,

Lina Sun,

Min Zhang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

Summary ADAR1 is a pivotal regulator in RNA-induced immune responses by catalyzing the conversion of adenosine to inosine on double-stranded RNA. Mutations are associated with human autoimmune disease, and targeting has been proposed for cancer immunotherapy. However, molecular mechanisms governing ADAR1-mediated RNA editing remain enigmatic. Here, we provide detailed biochemical structural characterizations ADAR1. Our profiling reveals that both sequence duplex length-dependent, but can well tolerate mismatches near site. Moreover, our high-resolution structures ADAR1-RNA complexes, coupled mutagenesis studies, revealed basis binding, substrate selection, dimerization, crucial role RNA-binding domain 3 editing. The also help explain potential defects disease-associated mutations, where RNA-sequencing analysis further indicate some mutations preferentially impact RNAs short duplex. findings illustrate mechanism clues deciphering its regulation drug targeting. HIGHLIGHTS Biochemical preference Atomic resolution two physiological substrates Disease-related dsRNA. essential capture

Language: Английский

Citations

0
Nuclear Retention and Rna Editing Suppress the Recognition of Undegraded Intron Lariats as Non-Self DOI
Keonyong Lee, Jayoung Ku,

Soo Young Park

et al.

Published: Jan. 1, 2025

Language: Английский

Citations

0
Leveraging genetics to understand ADAR1-mediated RNA editing in health and disease DOI
Jin Billy Li, Carl R. Walkley

Nature Reviews Genetics, Journal Year: 2025, Volume and Issue: unknown

Published: April 14, 2025

Language: Английский

Citations

0