Selective inhibition of ADAR2-catalyzed editing of the serotonin 2c receptor pre-mRNA by a helix-threading peptide

Schirle, N.T.; Goodman, Rena A.; Krishnamurthy, Malathy; Beal, Peter A.

doi:10.1039/c0ob00309c

Cited by 29 publications

(41 citation statements)

References 51 publications

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“…However, given the substrate promiscuity of ADARs, this strategy might lead to unpredictable outcome. Importantly, substrate-specific inhibition of editing is recently proposed to be feasible by a helix-threading peptide target (50). This will provoke more creative strategy development to restore editing balance in gene-specific manner.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

RNA Editome Imbalance in Hepatocellular Carcinoma

et al. 2014

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Adenosine-to-inosine conversion (A-to-I editing), a posttranscriptional modification on RNA, contributes to extensive transcriptome diversity. A-to-I editing is a hydrolytic deamination process, catalyzed by adenosine deAminase acting on double-stranded RNA (ADAR) family of enzymes. ADARs are essential for normal mammalian development, and disturbance in RNA editing has been implicated in various pathologic disorders, including cancer. Thanks to next-generation sequencing, rich databases of transcriptome evolution for cancer development at the resolution of single nucleotide have been generated. Extensive bioinformatic analysis revealed a complex picture of RNA editing change during transformation. Cancer displayed global hypoediting of Alurepetitive elements with gene-specific editing pattern. In particular, hepatocellular carcinoma editome is severely disrupted and characterized by hyper-and hypoediting of different genes, such as hyperedited AZIN1 (antizyme inhibitor 1) and FLNB (filamin B, b) and hypoedited COPA (coatomer protein complex, subunit a). In hepatocellular carcinoma, not only the recoding editing in exons, but also the editing in noncoding regions (e.g., Alu-repetitive elements and microRNA) displays such complex editing pattern with site-specific editing trend. In this review, we will discuss current research progress on the involvement of abnormal A-to-I editing in cancer development, more specifically on hepatocellular carcinoma. Cancer Res; 74(5); 1301-6. Ó2014 AACR.

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Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

RNA Editome Imbalance in Hepatocellular Carcinoma

et al. 2014

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“…21 A number of factors are known to contribute to ADAR specificity in vitro, including intra-and intermolecular base-pairing, 22 length of the dsRNA, 23 and the positioning of bulges, loops and mismatches within a duplex. 24,25 Consistent with this, imperfect base-pairing of short exonic regions with downstream intronic regions promotes editing of select adenosines within the coding regions of many ADAR target mRNAs in vivo. 26 This specificity is thought to arise from helical disruptions of imperfect base-pairing that limit the number of binding modes available to the dsRBDs of ADARs.…”

Section: Introductionmentioning

confidence: 78%

Noncoding regions ofC. elegansmRNA undergo selective adenosine to inosine deamination and contain a small number of editing sites per transcript

et al. 2015

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ADARs (Adenosine deaminases that act on RNA) "edit" RNA by converting adenosines to inosines within doublestranded regions. The primary targets of ADARs are long duplexes present within noncoding regions of mRNAs, such as introns and 3 0 untranslated regions (UTRs). Because adenosine and inosine have different base-pairing properties, editing within these regions can alter splicing and recognition by small RNAs. However, despite numerous studies identifying multiple editing sites in these genomic regions, little is known about the extent to which editing sites cooccur on individual transcripts or the functional output of these combinatorial editing events. To begin to address these questions, we performed an ultra-deep sequencing analysis of 4 Caenorhabditis elegans 3 0 UTRs that are known ADAR targets. Synchronous editing events were determined for the long duplexes in vivo. Furthermore, the validity of each editing event was confirmed by sequencing the same regions of mRNA from worms that lack A-to-I editing. This analysis identified a large number of editing sites that can occur within each 3 0 UTR, but interestingly, each individual transcript contained only a small fraction of these A-to-I editing events. In addition, editing patterns were not random, indicating that an editing event can affect the efficiency of editing at subsequent adenosines. Furthermore, we identified specific sites that can be both positively and negatively correlated with additional sites leading to mutually exclusive editing patterns. These results suggest that editing in noncoding regions is selective and hyper-editing of cellular RNAs is rare.

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“…RNA editing dysregulation can be rectified by restoring ADAR balance by overexpressing or silencing ADARs by shRNAs (small hairpin RNAs) or clustered regularly interspaced short palindromic repeats [35]. However, due to the widespread activity of RNA editing enzymes, reinstating a specific hyper-edited or hypoedited transcript by introducing a specific RNA-binding peptide [36] or locked nucleotide acids [37] would be more effective.…”

Section: Discussionmentioning

confidence: 99%