How do ADARs bind RNA? New protein‐RNA structures illuminate substrate recognition by the RNA editing ADARs

Thomas, Justin M.; Beal, Peter A.

doi:10.1002/bies.201600187

Cited by 48 publications

(44 citation statements)

References 42 publications

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“…An A:C mismatch at the editing site ("site_1_1:A:C") had a high relative contribution for NEIL1 (18.03%) and TTYH2 (15.95%) but contributed less to AJUBA editing levels (0.31%). The presence of A:C mismatch was strongly positively correlated with editing levels, consistent with previous proposals that it facilitates the flipping-out of the adenosine for ADAR editing 33,34 (Fig. 5f).…”

Section: Model Interpretation Provides Insights Into Common and Substsupporting

confidence: 90%

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Learning cis-regulatory principles of ADAR-based RNA editing from CRISPR-mediated mutagenesis

Liu

Sun

Shcherbina

et al. 2019

Preprint

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Adenosine-to-inosine (A-to-I) RNA editing catalyzed by ADAR enzymes occurs in double-stranded RNAs (dsRNAs). How the RNA sequence and structure (i.e., the cis-regulation) determine the editing efficiency and specificity is poorly understood, despite a compelling need towards functional understanding of known editing events and transcriptome engineering of desired adenosines. We developed a CRISPR/Cas9-mediated saturation mutagenesis approach to generate comprehensive libraries of point mutations near an editing site and its editing complementary sequence (ECS) at the endogenous genomic locus. We used machine learning to integrate diverse RNA sequence features and computationally predicted structures to model editing levels measured by deep sequencing and identified cis-regulatory features of RNA editing. As proof-of-concept, we applied this integrative approach to three editing substrates. Our models explained over 70% of variation in editing levels. The models indicate that RNA sequence and structure features synergistically determine the editing levels.Our integrative approach can be broadly applied to any editing site towards the goal of deciphering the RNA editing code. It also provides guidance for designing and screening of antisense RNA sequences that form dsRNA duplex with the target transcript for ADAR-mediated transcriptome engineering.

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Section: Model Interpretation Provides Insights Into Common and Substsupporting

confidence: 90%

“…5b), as these regions within the RNA substrate fully encompass the interaction site with the ADAR deaminase domain ( Fig. 5c) 33,34 . The 122 features were further grouped into nine major categories for purposes of feature interpretation ( Supplementary Fig.…”

Section: Machine Learning Models Accurately Predict Substrate-specifimentioning

confidence: 99%

Learning cis-regulatory principles of ADAR-based RNA editing from CRISPR-mediated mutagenesis

Liu

Sun

Shcherbina

et al. 2019

Preprint

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“…The deaminase domain also has an intrinsic affinity for dsRNA with limited sequence preference. The crystal structures of ADAR2 showed that the deaminase domain binds dsRNA with a highly localized distortion in RNA, causing flipping of the target adenosine base out of the RNA duplex and its insertion into the active site (126,127) (Figure 3b). While the mechanism for base flipping appears somewhat analogous to those of DNA methyltransferases (MTases) (128), ADAR2 and the DNA MTases flip their target bases through minor and major grooves, respectively, reflecting their differences in dsRNA-and dsDNA-binding modes.…”

Section: Adenosine Deaminases Acting On Rnamentioning

confidence: 99%

Double-Stranded RNA Sensors and Modulators in Innate Immunity

Hur

2019

Annu. Rev. Immunol.

274

286

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Detection of double-stranded RNAs (dsRNAs) is a central mechanism of innate immune defense in many organisms. We here discuss several families of dsRNA-binding proteins involved in mammalian antiviral innate immunity. These include RIG-I-like receptors, protein kinase R, oligoadenylate synthases, adenosine deaminases acting on RNA, RNA interference systems, and other proteins containing dsRNA-binding domains and helicase domains. Studies suggest that their functions are highly interdependent and that their interdependence could offer keys to understanding the complex regulatory mechanisms for cellular dsRNA homeostasis and antiviral immunity. This review aims to highlight their interconnectivity, as well as their commonalities and differences in their dsRNA recognition mechanisms. KeywordsdsRNA; RIG-I-like receptor; protein kinase R; oligoadenylate synthase; dsRNA-dependent adenosine deaminase; RNA interference HHS Public Access

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“…If the ADAR2 dsRBDs are positioned as on GluR2 Q/R substrate (Stefl et al 2010), then dsRBD2 in the minor groove 3 ′ of the edited A will make an extremely close approach to the deaminase domain here, where gln 488 enters the dsRNA to compensate the unpaired base partner of the edited adenosine. Thomas and Beal (2017) suggested that the deaminase domain-dsRBD2 steric clashes involved are too great to overcome. Nevertheless, the complex the deaminase domain alone forms with RNA may differ from that formed in the full-length protein.…”

Section: Effects Of Adar S and Adar G Isoforms On Editing And On Cns mentioning

confidence: 99%

ADAR RNA editing below the backbone

Keegan

Khan

Vukić

et al. 2017

RNA

147

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ADAR RNA editing enzymes (denosine eminases acting on NA) that convert adenosine bases to inosines were first identified biochemically 30 years ago. Since then, studies on ADARs in genetic model organisms, and evolutionary comparisons between them, continue to reveal a surprising range of pleiotropic biological effects of ADARs. This review focuses on, which has a single gene encoding a homolog of vertebrate ADAR2 that site-specifically edits hundreds of transcripts to change individual codons in ion channel subunits and membrane and cytoskeletal proteins. ADAR is involved in the control of neuronal excitability and neurodegeneration and, intriguingly, in the control of neuronal plasticity and sleep. ADAR also interacts strongly with RNA interference, a key antiviral defense mechanism in invertebrates. Recent crystal structures of human ADAR2 deaminase domain-RNA complexes help to interpret available information on ADAR isoforms and on the evolution of ADARs from tRNA deaminase ADAT proteins. ADAR RNA editing is a paradigm for the now rapidly expanding range of RNA modifications in mRNAs and ncRNAs. Even with recent progress, much remains to be understood about these groundbreaking ADAR RNA modification systems.

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How do ADARs bind RNA? New protein‐RNA structures illuminate substrate recognition by the RNA editing ADARs

Cited by 48 publications

References 42 publications

Learning cis-regulatory principles of ADAR-based RNA editing from CRISPR-mediated mutagenesis

Learning cis-regulatory principles of ADAR-based RNA editing from CRISPR-mediated mutagenesis

Double-Stranded RNA Sensors and Modulators in Innate Immunity

ADAR RNA editing below the backbone

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