The ADAR1 editome reveals drivers of editing-specificity for ADAR1-isoforms

Kleinová, Renata; Leuchtenberger, A. F.; Giudice, Claudio Lo; Tanzer, Andrea; Derdak, Sophia; Picardi, Ernesto; Jantsch, Michael F.

doi:10.1101/2021.11.24.469911

Cited by 4 publications

(4 citation statements)

References 71 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Azin1 carries two sites that are mostly edited by ADAR1 p150 [50,51]. Here, site 1 was edited to ∼25% by wild-type ADAR1 p150 while editing was almost completely abolished by the dimerization mutant (Figure 5A).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Dimerization of ADAR1 modulates site-specificity of RNA editing

Mboukou,

Rajendra,

Messmer

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

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

show abstract

Section: Resultsmentioning

confidence: 99%

“…Human ADAR1 plasmids were made as described in our previous studies [50]. All cloning and mutation procedures were done by NEBuilder HiFi DNA assembly according to the manufacturer's instructions.…”

Section: Plasmids For Hek293t and Hela Transfectionsmentioning

confidence: 99%

Dimerization of ADAR1 modulates site-specificity of RNA editing

Mboukou,

Rajendra,

Messmer

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Specifically, the cytoplasmic ADAR1p150 isoform negatively regulates the MDA5/MAVS pathway (Pestal et al, 2015). Recent work has illuminated editing sites of ADAR1 isoforms revealing that the ADAR1p150 isoform preferentially editing 3′‐UTRs while the ADAR1p110 isoform favoring intronic sites (Kleinova et al, 2023). In addition, ADAR1p150 edits a wider range of targets than ADAR1p110 (Sun et al, 2021, 2023).…”

Section: Introduction To Adarmentioning

confidence: 99%

A‐to‐I RNA editing by ADAR and its therapeutic applications: From viral infections to cancer immunotherapy

Datta,

Adamska,

Bhate

et al. 2023

WIREs RNA

View full text Add to dashboard Cite

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

show abstract

“…A non-classical nuclear localization signal (NLS) overlaps the third double-stranded RNA binding domain (dsRBD) in both isoforms (19–21). The localization of the different isoforms is thought to be one of the regulatory mechanisms affecting ADAR1 RNA editing activity (19, 22, 23). Although ADAR2 is nuclear, it can be sequestered into the nucleolus via an NLS found in its dsRBD (also in the N-terminus region of the enzyme) (24).…”

Section: Introductionmentioning

confidence: 99%

ADBP-1 regulates ADR-2 nuclear localization to control editing substrate selection

Eliad,

Schneider,

Zgayer

et al. 2023

Preprint

View full text Add to dashboard Cite

Adenosine-to-inosine (A-to-I) RNA editing, catalyzed by ADAR enzymes, is a prevalent and conserved RNA modification. While A-to-I RNA editing is essential in mammals, in Caenorhabditis elegans, it is not, making them invaluable for RNA editing research. ADR-2 is the sole A-to-I editing enzyme in C. elegans. Although ADAR localization is well-studied in humans, it is not well-established in C. elegans. In this study, we examine the cellular and tissue-specific localization of ADR-2. We show that while ADR-2 is present in most cells in the embryo, at later stages, the expression is both tissue- and cell-type-specific. Additionally, ADR-2 is present mainly in the nucleus, adjacent to the chromosomes, at all cell cycle stages. We showed that endogenous ADR-2 nuclear localization depends on ADBP-1 and not ADR-1, a prominent RNA editing regulator in C. elegans. In adbp-1 mutant worms, the mislocalization of ADR-2 leads to decreased editing levels as well as de-novo editing, mostly in exons, suggesting that ADR-2 is also functional in the cytoplasm. Besides, ADBP-1 absence affects gene expression. Furthermore, our analysis showed that ADR-2 targets adenosines with different surrounding nucleotides in exons and introns. Our findings indicate that ADR-2 cellular localization is highly regulated and affects its functions.

show abstract

The ADAR1 editome reveals drivers of editing-specificity for ADAR1-isoforms

Cited by 4 publications

References 71 publications

Dimerization of ADAR1 modulates site-specificity of RNA editing

Dimerization of ADAR1 modulates site-specificity of RNA editing

A‐to‐I RNA editing by ADAR and its therapeutic applications: From viral infections to cancer immunotherapy

ADBP-1 regulates ADR-2 nuclear localization to control editing substrate selection

Contact Info

Product

Resources

About