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

SLIRP amplifies antiviral signaling via positive feedback regulation and contributes to autoimmune diseases DOI
Doyeong Ku,

Yewon Yang,

Young-Ran Park

et al.

Cell Reports, Journal Year: 2025, Volume and Issue: 44(5), P. 115588 - 115588

Published: April 19, 2025

Language: Английский

Citations

0
Generation of a newAdar1p150−/−mouse demonstrates isoform-specific roles in embryonic development and adult homeostasis DOI Open Access
Zhen Liang,

Ankita Goradia,

Carl R. Walkley

et al.

RNA, Journal Year: 2023, Volume and Issue: 29(9), P. 1325 - 1338

Published: June 8, 2023

The RNA editing enzyme adenosine deaminase acting on 1 (ADAR1) is an essential regulator of the innate immune response to both cellular and viral double-stranded (dsRNA). Adenosine-to-inosine (A-to-I) by ADAR1 modifies sequence structure endogenous dsRNA masks it from cytoplasmic sensor melanoma differentiation-associated protein 5 (MDA5), preventing activation. Loss-of-function mutations in ADAR are associated with rare autoinflammatory disorders including Aicardi-Goutières syndrome (AGS), defined a constitutive systemic up-regulation type I interferon (IFN). murine Adar gene encodes two isoforms distinct functions: ADAR1p110 constitutively expressed localizes nucleus, whereas ADAR1p150 primarily inducible IFN. Recent studies have demonstrated critical requirement for suppress activation self dsRNAs. However, detailed vivo characterization role during development adult mice lacking. We identified new ADAR1p150-specific knockout mouse mutant based single nucleotide deletion that resulted loss without affecting expression. Adar1p150-/- died embryonically at E11.5-E12.5 accompanied cell death fetal liver activated IFN response. Somatic adults was lethal caused rapid hematopoietic failure, demonstrating ongoing vivo. generation this model demonstrates provides tool dissecting functional differences between their physiological contributions.

Language: Английский

Citations

10
Retrotransposon life cycle and its impacts on cellular responses DOI Creative Commons
Ahmad Luqman-Fatah,

Kei Nishimori,

Shota Amano

et al.

RNA Biology, Journal Year: 2024, Volume and Issue: 21(1), P. 11 - 27

Published: Oct. 13, 2024

Approximately 45% of the human genome is comprised transposable elements (TEs), also known as mobile genetic elements. However, their biological function remains largely unknown. Among them, retrotransposons are particularly abundant, and some copies still capable mobilization within through RNA intermediates. This review focuses on life cycle summarizes regulatory mechanisms impacts cellular processes. Retrotransposons generally epigenetically silenced in somatic cells, but transcriptionally reactivated under certain conditions, such tumorigenesis, development, stress, ageing, potentially leading to instability. We explored dual nature genomic parasites elements, focusing roles diversity innate immunity. Furthermore, we discuss how host factors regulate retrotransposon cDNA intermediates binding, modification, degradation. The interplay between machinery provides insight into complex regulation potential for dysregulation cause aberrant responses inflammation autoimmune diseases.

Language: Английский

Citations

3
Mouse models for understanding physiological functions of ADARs DOI
Qinyi Zhang, Carl R. Walkley

Methods in enzymology on CD-ROM/Methods in enzymology, Journal Year: 2025, Volume and Issue: unknown, P. 153 - 185

Published: Jan. 1, 2025

Language: Английский

Citations

0
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

Citations

0