RNA Editing by Mammalian ADARs

Hogg, Marion C.; Paro, Simona; Keegan, Liam P.; O’Connell, Mary A.

doi:10.1016/b978-0-12-380860-8.00003-3

Cited by 105 publications

(87 citation statements)

References 122 publications

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“…These enzymes convert adenosines to inosines by hydrolytic deamination in structured and doublestranded RNA substrates (16,17). Inosines formed by adenosine deamination can alter the coding potential of mRNAs but also can affect splicing, localization, or transport of cellular and viral RNAs (16,17).…”

mentioning

confidence: 99%

A bimodular nuclear localization signal assembled via an extended double-stranded RNA-binding domain acts as an RNA-sensing signal for transportin 1

Barraud¹,

Banerjee

Mohamed³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The human RNA-editing enzyme adenosine deaminase acting on RNA (ADAR1) carries a unique nuclear localization signal (NLS) that overlaps one of its double-stranded RNA-binding domains (dsRBDs). This dsRBD-NLS is recognized by the nuclear import receptor transportin 1 (Trn1; also called karyopherin-β2) in an RNA-sensitive manner. Most Trn1 cargos bear a well-characterized proline-tyrosine-NLS, which is missing from the dsRBD-NLS. Here, we report the structure of the dsRBD-NLS, which reveals an unusual dsRBD fold extended by an additional Nterminal α-helix that brings the N-and C-terminal flanking regions in close proximity. We demonstrate experimentally that the atypical ADAR1-NLS is bimodular and is formed by the combination of the two flexible fragments flanking the folded domain. The intervening dsRBD acts only as an RNA-sensing scaffold, allowing the two NLS modules to be properly positioned for interacting with Trn1. We also provide a structural model showing how Trn1 can recognize the dsRBD-NLS and how dsRNA binding can interfere with Trn1 binding.NMR | RNA-binding protein | nucleocytoplasmic shuttling |

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mentioning

confidence: 99%

A bimodular nuclear localization signal assembled via an extended double-stranded RNA-binding domain acts as an RNA-sensing signal for transportin 1

Barraud¹,

Banerjee

Mohamed³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…The adenosine deaminase reaction catalyzed by ADAR2 is site-specific (21), as demonstrated in studies of the GluA2 subunit of glutamate AMPA receptor (21)(22)(23), in which the conversion of a glutamine (Q) to an arginine (R) codon is exclusively mediated by ADAR2 (23). ADAR2 activity is essential for brain development and function (24), and >99.9% of RNA editing occurs at the Q/R site of GluA2 in the human central nervous system (25). In addition, RNA editing plays a role in controlling microRNA (miRNA) biogenesis (26).…”

Section: Rna Editing Was First Identified In Trypanosomes Bymentioning

confidence: 99%

Splicing variants of ADAR2 and ADAR2-mediated RNA editing in glioma

Zhao

et al. 2016

Oncology Letters

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Abstract. The roles of alternative splicing and RNA editing in gene regulation and transcriptome diversity are well documented. Adenosine deaminases acting on RNA (ADARs) are responsible for adenosine-to-inosine (A-to-I) editing and exemplify the complex association between RNA editing and alternative splicing. The self-editing activity of ADAR2, which acts on its own pre-mRNA, leads to its alternative splicing. Alternative splicing occurs independently at nine splicing sites on ADAR2 pre-mRNA, generating numerous alternative splicing variants with various catalytic activities. A-to-I RNA editing is important in a range of physiological processes in humans and is associated with several diseases, including amyotrophic lateral sclerosis, mood disorders, epilepsy and glioma. Reduced editing at the glutamine/arginine site of the AMPA receptor subunit GluA2 in glioma, without any alteration in ADAR2 expression, is a notable phenomenon. Several studies have tried to explain this alteration in the catalytic activity of ADAR2; however, the underlying mechanism remains unclear. The present review summarizes the relevant literature and shares experimental results concerning ADAR2 alternative splicing. In particular, the present review demonstrates that shifts in the relative abundance of the active and inactive splicing variants of ADAR2 may reduce the ADAR2 editing activity in glioma. Dominant expression of ADAR2 splicing variant with low enzyme activity causes reduced RNA editing of GluA2 subunit at the glutamine/arginine site in glioma.

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“…13 Three vertebrate ADAR gene family members (ADAR1-3) share common structural features, such as the presence of multiple dsRNA-binding domains (dsRBDs) and a separate deaminase domain. 2,3 In contrast to viable ADAR2-null and ADAR3-null mutant mice, 14 ADAR1-null mouse embryos die prenatally due to widespread apoptosis, 15,16 indicating the requirement of ADAR1 for life. However, the mechanism that underlies the ADAR1-null mouse phenotype is unknown.…”

Section: Antagonistic and Stimulative Roles Of Adar1 In Rna Silencingmentioning

confidence: 99%

“…[1][2][3] In a few cases, A-to-I RNA editing of mRNA results in recoding and functional diversification of a select group of neurotransmitters and ion channels. [4][5][6] However, A-to-I editing occurs most frequently in non-coding regions that contain repetitive elements such as SINE and LINE.…”

Section: Antagonistic and Stimulative Roles Of Adar1 In Rna Silencingmentioning

confidence: 99%

Antagonistic and stimulative roles of ADAR1 in RNA silencing

et al. 2013

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A denosine deaminases acting on RNA (ADARs) are involved in RNA editing that converts adenosine residues to inosine specifically in double-stranded RNAs (dsRNA). This A-to-I RNA editing pathway and the RNA interference (RNAi) pathway seem to interact antagonistically by competing for their common dsRNA substrates. For instance, A-to-I editing of certain microRNA (miRNA) precursors by ADAR1 and ADAR2 inhibits their processing to mature miRNAs. Recent studies unexpectedly revealed the presence of a completely different type of interaction between the RNA editing mechanism and the RNAi machinery. ADAR1 forms a complex via direct protein-protein interaction with Dicer, an RNase III gene family member involved in the RNAi mechanism. ADAR1 in the Dicer complex promotes pre-miRNA cleavage by Dicer and facilitates loading of miRNA onto RNAinduced silencing complexes, giving rise to an unsuspected stimulative function of ADAR1 on miRNA processing and RNAi mechanisms. ADAR1 differentiates its functions in RNA editing and RNAi by formation of either ADAR1-ADAR1 homodimer or Dicer-ADAR1 heterodimer complexes. Expression of miRNAs is globally inhibited in ADAR1-null mouse embryos, which, in turn, alters expression of their target genes and may contribute to their embryonic lethal phenotype.

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RNA Editing by Mammalian ADARs

Cited by 105 publications

References 122 publications

A bimodular nuclear localization signal assembled via an extended double-stranded RNA-binding domain acts as an RNA-sensing signal for transportin 1

A bimodular nuclear localization signal assembled via an extended double-stranded RNA-binding domain acts as an RNA-sensing signal for transportin 1

Splicing variants of ADAR2 and ADAR2-mediated RNA editing in glioma

Antagonistic and stimulative roles of ADAR1 in RNA silencing

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