Expression and Regulation by Interferon of a Double-Stranded-RNA-Specific Adenosine Deaminase from Human Cells: Evidence for Two Forms of the Deaminase

Patterson, John B.; Samuel, Charles E.

doi:10.1128/mcb.15.10.5376

Cited by 511 publications

(635 citation statements)

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“…In Drosophila, ADAR can edit its own pre-mRNA (Palladino et al, 2000a), whereas in mammals a self-editing process leads to alternative splicing of ADAR2 (Rueter et al, 1999). Furthermore, ADAR1 expression in mammals is regulated by interferon (Patterson and Samuel, 1995).In this work we demonstrate that ADAR1 is modified by SUMO at lysine residue 418. Substitution of this amino acid residue by arginine, which cannot be modified by SUMO, affects the editing activity of the enzyme.…”

mentioning

confidence: 60%

Section: Introductionmentioning

confidence: 99%

“…ADAR1 differs from the other members of the family in its extended N-terminus that is enriched in RG residues and contains two tandemly arranged Z-DNA-binding domains (Keegan et al, 2001. In humans, there are two ADAR1 forms: a 150-kDa protein (comprising amino acids 1-1226) that is induced by interferon and localizes predominantly in the cytoplasm, and a 110-kDa protein (encompassing residues 296-1226) that is constitutively expressed and localizes to the nucleus (Patterson and Samuel, 1995;George and Samuel, 1999b, a). Several lines of evidence suggest that ADAR activity is tightly controlled in the cell.…”

Section: Introductionmentioning

confidence: 99%

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SUMO-1 Modification Alters ADAR1 Editing Activity

Desterro

Keegan

Jaffray

et al. 2005

MBoC

104

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We identify ADAR1, an RNA-editing enzyme with transient nucleolar localization, as a novel substrate for sumoylation. We show that ADAR1 colocalizes with SUMO-1 in a subnucleolar region that is distinct from the fibrillar center, the dense fibrillar component, and the granular component. Our results further show that human ADAR1 is modified by SUMO-1 on lysine residue 418. An arginine substitution of K418 abolishes SUMO-1 conjugation and although it does not interfere with ADAR1 proper localization, it stimulates the ability of the enzyme to edit RNA both in vivo and in vitro. Moreover, modification of wild-type recombinant ADAR1 by SUMO-1 reduces the editing activity of the enzyme in vitro. Taken together these data suggest a novel role for sumoylation in regulating RNA-editing activity. INTRODUCTIONA defining feature of eukaryotic cells is the generation of protein diversity either posttranscriptionally by alternative splicing and RNA editing or posttranslationally by modification of amino acids in proteins. One of the most recently discovered posttranslational modification mechanism in eukaryotes involves the covalent attachment of the small ubiquitinlike modifier, SUMO, to target proteins. Modification of proteins by SUMO, or sumoylation, plays crucial regulatory roles in eukaryotes. Proteins known to be modified by SUMO include, among others, RanGAP1, PCNA, I B␣, p53, c-jun, topoisomerases, promyelocytic leukemia protein (PML), Sp100, and the mitogen-activated protein kinase kinase 1 (MEKK1). Many SUMO substrates are transcription factors and cofactors, or proteins implicated in DNA repair and replication (reviewed by Hay, 2001;Melchior et al., 2003;Seeler and Dejean, 2003;Hay, 2005). Although it is well established that SUMO can affect target protein function by altering its subcellular localization, activity, or stability, for many substrates the biological functions of sumoylation remain unknown.Sumoylation is a reversible and highly dynamic process that involves formation of an isopeptide bond between the C-terminus of SUMO and the ⑀-amino group of a lysine residue of the target protein. The most intensely studied human form of SUMO is the SUMO-1 protein, which is 48% identical to yeast Smt3 (Bayer et al., 1998;Mossessova and Lima, 2000). In vertebrates there are at least three additional proteins. SUMO-2 and SUMO-3 are ϳ45% identical to SUMO-1 (Saitoh and Hinchey, 2000), and SUMO-4 shows an 86% amino acid homology to SUMO-2 (Bohren et al., 2004). SUMO is conjugated to protein substrates via an ATP-dependent enzymatic pathway that is mechanistically similar to ubiquitination. The reaction requires a SUMO protease that removes four amino acids from the C-terminus of the 101-amino acid SUMO-1 precursor to generate the mature form; an heterodimeric SUMO-activating enzyme, SAE1/2; Ubc9, a SUMO-conjugating enzyme that ligates directly to its protein target; and an E3-like SUMO ligase (reviewed Melchior et al., 2003). Three SUMO E3s have been identified so far: the mammalian protein inhibitors of activated S...

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confidence: 60%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SUMO-1 Modification Alters ADAR1 Editing Activity

Desterro

Keegan

Jaffray

et al. 2005

MBoC

104

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“…Two isoforms of ADAR1, a full-length ADAR1L and a shorter, N-terminaltruncated ADAR1S, are known 40 . One of the three promoters that drive the ADAR1 gene is interferon inducible, and the mRNA transcribed from this promoter directs the translation of ADAR1L, initiated from an upstream Met codon 41 .…”

Section: Adar Gene Expression and Regulationmentioning

confidence: 99%

“…2a). ADAR2 expression is regulated by the transcriptional activator cyclic-AMP-response-element binding (CREB) protein 43 , but the regulatory mechanism for ADAR3 is currently unknown.ADAR1L is detected mainly in the cytoplasm, whereas ADAR1S localizes in the nucleoplasm and nucleolus 40,44,45 . ADAR2 localizes predominantly in the nucleolus 44,46 .…”

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confidence: 98%

Editor meets silencer: crosstalk between RNA editing and RNA interference

Nishikura

2006

Nat Rev Mol Cell Biol

257

263

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The most prevalent type of RNA editing is mediated by ADAR (adenosine deaminase acting on RNA) enzymes, which convert adenosines to inosines (a process known as A→I RNA editing) in double-stranded (ds)RNA substrates. A→I RNA editing was long thought to affect only selected transcripts by altering the proteins they encode. However, genome-wide screening has revealed numerous editing sites within inverted Alu repeats in introns and untranslated regions. Also, recent evidence indicates that A→I RNA editing crosstalks with RNA-interference pathways, which, like A→I RNA editing, involve dsRNAs. A→I RNA editing therefore seems to have additional functions, including the regulation of retrotransposons and gene silencing, which adds a new urgency to the challenges of fully understanding ADAR functions.An RNA transcript is subjected to various maturation processes, such as 5′ capping, splicing, 3′ processing and polyadenylation, after it is transcribed from the gene. Post-transcriptional processing of primary transcripts is essential to generate mature messenger RNAs that are ready to be translated into proteins 1 . RNA editing is a post-transcriptional-processing mechanism that results in an RNA sequence that is different from the one encoded by the genome, and thereby contributes to the diversity of gene products. There are different types of RNA-editing mechanism that either add or delete nucleotides, or that change one nucleotide into another 2 (BOX 1).The type of RNA editing that is most prevalent in higher eukaryotes converts adenosine (A) residues into inosine (I) in double-stranded (ds)RNAs through the action of ADAR (adenosine deaminase acting on RNA) enzymes [3][4][5] . A→I RNA editing of a short dsRNA that has formed between a coding exon and nearby intron sequences can lead to a codon change and an alteration in the protein function. However, it was recently discovered that the most frequent targets of A→I RNA editing seem to be long, but partially double-stranded, RNAs that are formed from inverted Alu repeats and long interspersed element (LINE) repeats located in introns and untranslated regions (UTRs) of mRNAs [6][7][8][9] . Global editing of non-coding RNA might control the expression of genes that harbour these repeat sequences of retrotransposon origin.Post-transcriptional gene regulation can also occur through RNA interference (RNAi), an evolutionarily conserved phenomenon that involves dsRNA molecules 10,11 . Small interfering RNAs (siRNAs) and microRNAs (miRNAs) are non-coding RNAs that are generated by a class of RNase III ribonucleases (specifically, Dicer and Drosha). These small RNAs are incorporated into the RNA-induced silencing complex (RISC), which mediates the RNAi process [12][13][14][15][16] . The idea that the RNAi and A→I RNA editing pathways might compete for a Competing interests statement: The author declares no competing financial interests. [23][24][25] . NIH Public AccessIn this review, I discuss recent findings on new functions of A→I RNA editing in the regulation of non...

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K160 in the RNA‐binding domain of the orf virus virulence factor OV20.0 is critical for its functions in counteracting host antiviral defense

Liao

Tseng

et al. 2021

FEBS Letters

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The OV20.0 virulence factor of orf virus antagonizes host antiviral responses. One mechanism through which it functions is by inhibiting activation of the dsRNA-activated protein kinase R (PKR) by sequestering dsRNA and by physically interacting with PKR. Sequence alignment indicated that several key residues critical for dsRNA binding were conserved in OV20.0, and their contribution to OV20.O function was investigated in this study. We found that residues F141, K160, and R164 were responsible for the dsRNA-binding ability of OV20.0. Interestingly, mutation at K160 (K160A) diminished the OV20.0-PKR interaction and further reduced the inhibitory effect of OV20.0 on PKR activation. Nevertheless, OV20.0 homodimerization was not influenced by K160A. The contribution of the dsRNA-binding domain and K160 to the suppression of RNA interference by OV20.0 was further demonstrated in plants. In summary, K160 is essential for the function of OV20.0, particularly its interaction with dsRNA and PKR that ultimately contributes to the suppression of PKR activation.

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Expression and Regulation by Interferon of a Double-Stranded-RNA-Specific Adenosine Deaminase from Human Cells: Evidence for Two Forms of the Deaminase

Cited by 511 publications

References 69 publications

SUMO-1 Modification Alters ADAR1 Editing Activity

SUMO-1 Modification Alters ADAR1 Editing Activity

Editor meets silencer: crosstalk between RNA editing and RNA interference

K160 in the RNA‐binding domain of the orf virus virulence factor OV20.0 is critical for its functions in counteracting host antiviral defense

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