Synthetic substrate analogs for the RNA-editing adenosine deaminase ADAR-2

Yi-Brunozzi, Hye Young; Easterwood, LaHoma M.; Kamilar, Gregg M.; Beal, Peter A.

doi:10.1093/nar/27.14.2912

Cited by 52 publications

(62 citation statements)

References 22 publications

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“…4). Ribose methylation of this adenosine should dramatically hamper its deamination to inosine (38). However, we have not been able so far to demonstrate such a role for MBII-52 in a negative control of the serotonin 5-HT 2C receptor mRNA editing, but this may be due to technical limitations (data not shown).…”

Section: Resultsmentioning

confidence: 87%

Identification of brain-specific and imprinted small nucleolar RNA genes exhibiting an unusual genomic organization

Cavaillé

Buiting

Kiefmann

et al. 2000

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

536

556

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We have identified three C͞D-box small nucleolar RNAs (snoRNAs) and one H͞ACA-box snoRNA in mouse and human. In mice, all four snoRNAs (MBII-13, MBII-52, MBII-85, and MBI-36) are exclusively expressed in the brain, unlike all other known snoRNAs. Two of the human RNA orthologues (HBII-52 and HBI-36) share this expression pattern, and the remainder, HBII-13 and HBII-85, are prevalently expressed in that tissue. In mice and humans, the brain-specific H͞ACA box snoRNA (MBI-36 and HBI-36, respectively) is intronencoded in the brain-specific serotonin 2C receptor gene. The three human C͞D box snoRNAs map to chromosome 15q11-q13, within a region implicated in the Prader-Willi syndrome (PWS), which is a neurogenetic disease resulting from a deficiency of paternal gene expression. Unlike other C͞D box snoRNAs, two snoRNAs, HBII-52 and HBII-85, are encoded in a tandemly repeated array of 47 or 24 units, respectively. In mouse the homologue of HBII-52 is processed from intronic portions of the tandem repeats. Interestingly, these snoRNAs were absent from the cortex of a patient with PWS and from a PWS mouse model, demonstrating their paternal imprinting status and pointing to their potential role in the etiology of PWS. Despite displaying hallmarks of the two families of ubiquitous snoRNAs that guide 2-O-ribose methylation and pseudouridylation of rRNA, respectively, they lack any telltale rRNA complementarity. Instead, brain-specific C͞D box snoRNA HBII-52 has an 18-nt phylogenetically conserved complementarity to a critical segment of serotonin 2C receptor mRNA, pointing to a potential role in the processing of this mRNA. T he biogenesis of eukaryotic ribosomes involves a complex rRNA processing pathway mostly taking place in a specialized subnuclear compartment, the nucleolus. Pre-rRNA maturation includes, in addition to a series of endonucleolytic and exonucleolytic cleavages, the covalent modification of a definite subset of rRNA nucleotides, essentially by 2Ј-O-ribose methylation and pseudouridylation. Each of these modifications is found at about 100 sites per vertebrate ribosome (1). Although these modifications are phylogenetically conserved and restricted to the most highly conserved and functionally important regions of rRNA, their function remains largely unknown. Spliceosomal small nuclear RNAs (snRNAs) also contain a number of conserved 2Ј-Omethylated nucleotides and pseudouridines, confined to snRNA sequences critical for splicing, i.e., involved in contacts with premRNA or other snRNAs (2). Remarkably, nucleotide modifications in the 5Ј terminal region of U2 snRNA are required for assembly of a functional U2 sn-ribonucleoprotein particle (3).The nucleolus contains a large number of small, metabolically stable RNAs, termed small nucleolar RNAs (snoRNAs) that fall into two major classes, the C͞D box and H͞ACA box snoRNAs, designated after common sequence motifs involved in the assembly of sno-ribonucleoprotein particles. Although each class includes a small number of snoRNAs required for definite pre-rRNA cl...

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Section: Resultsmentioning

confidence: 87%

Identification of brain-specific and imprinted small nucleolar RNA genes exhibiting an unusual genomic organization

Cavaillé

Buiting

Kiefmann

et al. 2000

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

536

556

View full text Add to dashboard Cite

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“…Although subtle determinants of ADAR specificity have been identified in the DRBMs (46), the primary determinants of ADAR site specificity are thought to reside in the characteristics of their dsRNA substrates (38,47). Structural selectivity of ADARs for a particular adenosine in the duplex is thought to be imparted by the pattern of bulges and base-pairing regions in the dsRNA, combined with the overall thermodynamic stability of the RNA (20,21,46,48). According to observations made using artificial substrates, internal loops of greater than six nucleotides define subdomains of ADAR action (22).…”

Section: Discussionmentioning

confidence: 99%

Structure and Sequence Determinants Required for the RNA Editing of ADAR2 Substrates

Dawson¹,

Sansam

Emeson

2004

Journal of Biological Chemistry

119

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ADAR2 is a double-stranded RNA-specific adenosine deaminase involved in the editing of mammalian RNAs by the site-specific conversion of adenosine to inosine. We have demonstrated previously that ADAR2 can modify its own pre-mRNA, leading to the creation of a proximal 3-splice junction containing a non-canonical adenosine-inosine (A-I) dinucleotide. Alternative splicing to this proximal acceptor shifts the reading frame of the mature mRNA transcript, resulting in the loss of functional ADAR2 expression. Both evolutionary sequence conservation and mutational analysis support the existence of an extended RNA duplex within the ADAR2 pre-mRNA formed by base-pairing interactions between regions ϳ1.3-kilobases apart in intron 4 and exon 5. Characterization of ADAR2 pre-mRNA transcripts isolated from adult rat brain identified 16 editing sites within this duplex region, and sites preferentially modified by ADAR1 and ADAR2 have been defined using both tissue culture and in vitro editing systems. Statistical analysis of nucleotide sequences surrounding edited and non-edited adenosine residues have identified a nucleotide sequence bias correlating with ADAR2 site preference and editing efficiency. Among a mixed population of ADAR substrates, ADAR2 preferentially favors its own transcript, yet mutation of a poor substrate to conform to the defined nucleotide bias increases the ability of that substrate to be modified by ADAR2. These data suggest that both sequence and structural elements are required to define adenosine moieties targeted for specific ADAR2-mediated deamination.

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“…In line with this notion, one of the brain-specific C/D box snoRNAs recently reported in mouse, MBII-52, contains a long (18-nt) phylogenetically conserved antisense element directed against a brain-specific mRNA encoding a serotonin receptor (17). Remarkably, the mRNA nucleotide predicted to be methylated by MBII-52 snoRNA is an adenosine undergoing conversion to inosine (50), suggesting that the snoRNA is involved in a control of the editing process, since methylation of an adenosine to be edited strongly inhibits its deamination in vitro (51). In this hypothesis, the presence of inosine at tissuespecific levels, particularly elevated in brain mRNAs (52), hints at the possibility that additional brain-specific box C/D snoRNAs with long complementarities to brain mRNAs still await identification.…”

Section: Rat Brain-specific Box C/d Snorna In Repeated Intronsmentioning

confidence: 99%

A Novel Brain-specific Box C/D Small Nucleolar RNA Processed from Tandemly Repeated Introns of a Noncoding RNA Gene in Rats

Cavaillé¹,

Vitali²,

Basyuk

et al. 2001

Journal of Biological Chemistry

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Antisense box C/D small nucleolar RNAs (snoRNAs) guide the 2-O-ribose methylations of eukaryotic rRNAs and small nuclear RNAs (snRNAs) through formation of a specific base pairing at each RNA methylation site. By analysis of a box C/D snoRNA cDNA library constructed from rat brain RNAs, we have identified a novel box C/D snoRNA, RBII-36, which is devoid of complementarity to rRNA or an snRNA and exhibits a brain-specific expression pattern. It is uniformly expressed in all major areas of adult rat brain (except for choroid plexus) and throughout rat brain ontogeny but exclusively detected in neurons in which it exhibits a nucleolar localization. In vertebrates, known methylation guide snoRNAs are intron-encoded and processed from transcripts of housekeeping genes. In contrast, RBII-36 snoRNA is intron-encoded in a gene preferentially expressed in the rat central nervous system and not in proliferating cells. Remarkably, this host gene, which encodes a previously reported noncoding RNA, Bsr, spans tandemly repeated 0.9-kilobase units including the snoRNA-containing intron. The novel brain-specific snoRNA appears to result not only from processing of the debranched lariat but also from endonucleolytic cleavages of unspliced Bsr RNA (i.e. an alternative splicing-independent pathway unreported so far for mammalian intronic snoRNAs). Sequences homologous to RBII-36 snoRNA were exclusively detected in the Rattus genus of rodents, suggesting a very recent origin of this brain-specific snoRNA.In eukaryotic cells, ribosome biogenesis takes place mainly in the nucleolus, through a series of intricate steps including (i) rDNA transcription by the cognate RNA polymerase I, (ii) processing of the pre-rRNA transcript by endo-and exonucleases and covalent modification of a subset of pre-rRNA nucleotides, (iii) packaging of pre-rRNA by ribosomal proteins, and (iv) cytoplasmic export of ribosomal subunits. Pre-rRNA maturation involves a large number of small nucleolar ribonucleoprotein particles (snoRNPs), 1 which can be defined as a metabolically stable association between small nucleolar RNA (snoRNA) and a specific set of proteins (1). All snoRNAs to date (except the RNA component for RNase MRP) fall into two major classes, box C/D and box H/ACA snoRNAs, based on the presence of short consensus sequence motifs (2). Whereas a few of them are involved in pre-rRNA nucleolytic cleavages, most box C/D and box H/ACA snoRNAs play a key role in specifying the two major types of rRNA nucleotide modification (2Ј-O-ribose methylations and pseudouridylations, respectively) through formation of a specific RNA duplex at the modification site (3-6). While function(s) of these nucleotide modifications are still elusive they are proposed to fine tune rRNA folding and interactions with ribosomal proteins. Thereby, they could play a role in the biogenesis and activity of mature cytoplasmic ribosomes, particularly with regard to their peptidyl transferase activities (7). Antisense box C/D snoRNAs contain conserved sequence motifs box C (5Ј-RUGAUG...

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Synthetic substrate analogs for the RNA-editing adenosine deaminase ADAR-2

Cited by 52 publications

References 22 publications

Identification of brain-specific and imprinted small nucleolar RNA genes exhibiting an unusual genomic organization

Identification of brain-specific and imprinted small nucleolar RNA genes exhibiting an unusual genomic organization

Structure and Sequence Determinants Required for the RNA Editing of ADAR2 Substrates

A Novel Brain-specific Box C/D Small Nucleolar RNA Processed from Tandemly Repeated Introns of a Noncoding RNA Gene in Rats

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