Circular RNAs (circRNAs) are a new class of non-coding RNAs formed by covalently closed loops through backsplicing. Recent methodologies have enabled in-depth characterization of circRNAs for identification and potential functions. CircRNAs play important roles in various biological functions as microRNA sponges, transcriptional regulators and combining with RNA binding proteins. Recent studies indicated that some cytoplasmic circRNAs can be effectively translated into detectable peptides, which enlightened us on the importance of circRNAs in cellular physiology function. Internal Ribosome Entry site (IRES)-and N 6-methyladenosines (m 6 A)-mediated cap-independent translation initiation have been suggested to be potential mechanism for circRNA translation. To date, several translated circRNAs have been uncovered to play pivotal roles in human cancers. In this review, we introduced the properties and functions of circRNAs, and characterized the possible mechanism of translation initiation and complexity of the translation ability of circRNAs. We summarized the emerging functions of circRNA-encoded proteins in human cancer. The works on circRNA translation will open a hidden human proteome, and enhance us to understand the importance of circRNAs in human cancer, which has been poorly explored so far.

The virus-associated VAI RNA of adenovirus is a small highly structured RNA that is required for the efficient translation of cellular and viral mRNAs at late times after infection. VAI RNA antagonizes the activation of the interferon-inducible RNA-dependent protein kinase, PKR, an important regulator of translation. The RNA-specific adenosine deaminase, ADAR, is an interferon-inducible RNA-editing enzyme that catalyzes the site-selective C-6 deamination of adenosine to inosine. ADAR possesses three copies of the highly conserved RNA-binding motif (dsRBM) that are similar to the two copies found in PKR, the enzyme in which the prototype dsRBM motif was discovered. We have examined the effect of VAI RNA on ADAR function. VAI RNA impairs the activity of ADAR deaminase. This inhibition can be observed in extracts prepared from interferon-treated human cells and from monkey COS cells in which wild-type recombinant ADAR was expressed. Analysis of wild-type and mutant forms of VA RNA suggests that the central domain is important in the antagonism of ADAR activity. These results suggest that VAI RNA may modulate viral and cellular gene expression by modulating RNA editing as well as mRNA translation.

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The RNA-specific adenosine deaminase (ADAR1) and the RNA-dependent protein kinase (PKR) are both interferon-inducible doublestranded (ds) RNA-binding proteins. ADAR1, an RNA editing enzyme that converts adenosine to inosine, possesses three copies of a dsRNA-binding motif (dsRBM). PKR, a regulator of translation, has two copies of the highly conserved dsRBM motif. To assess the functional selectivity of the dsRBM motifs in ADAR1, we constructed and characterized chimeric proteins in which the dsRBMs of ADAR1 were substituted with those of PKR. Recombinant PKR-ADAR1 chimeras retained significant RNA adenosine deaminase activity measured with a synthetic dsRNA substrate when the spacer region between the RNA-binding and catalytic domains of the deaminase was exactly preserved. However, with natural substrates, substitution of the first two dsRBMs of ADAR1 with those from PKR dramatically reduced site-selective editing activity at the R͞G and (؉)60 sites of the glutamate receptor B subunit pre-RNA and completely abolished editing of the serotonin 2C receptor (5-HT 2CR) pre-RNA at the A site. Chimeric deaminases possessing only the two dsRBMs from PKR were incapable of editing either glutamate receptor B subunit or 5-HT 2CR natural sites but edited synthetic dsRNA. Finally, RNA antagonists of PKR significantly inhibited the activity of chimeric PKR-ADAR1 proteins relative to wild-type ADAR1, further demonstrating the functional selectivity of the dsRBM motifs.T he RNA-specific adenosine deaminases (ADAR) (1) constitute a multigene family of editing enzymes. They catalyze the C-6 deamination of adenosine to produce inosine in double-stranded (ds) structures present within cellular pre-RNAs and viral RNAs as well as synthetic dsRNA substrates (2-6). So far, two functional RNA adenosine deaminases, denoted ADAR1 and ADAR2, have been described (1, 6). We isolated molecular cDNA clones of ADAR1 as an interferon-inducible enzyme (7,8). The ADAR1 protein possesses both dsRNA-binding and Z-DNA-binding properties (8)(9)(10)(11)(12)(13)(14). The dsRNA-binding domain of the 1,226-aa ORF of the ADAR1 cDNA consists of three copies of the highly conserved dsRNA-binding motif (dsRBM). The prototype dsRBM including the R core amino acid residues was first identified in the interferoninducible RNA-dependent protein kinase PKR, an enzyme that plays a pivotal role in the antiviral actions of IFN and the control of translation in virus-infected cells (15,16). PKR possesses two copies of the dsRBM that cannot substitute for each other (17)(18)(19)(20). RNAs bound by PKR via the dsRBMs mediate the autophosphorylation and activation of PKR (19,21), thereby leading to the subsequent phosphorylation of the ␣ subunit of protein synthesis initiation factor eIF-2 (22, 23).Three naturally occurring splice variant isoforms of human ADAR1 are known that are differentially expressed in different tissues (24). In comparison to the full-length 1,226-aa ADAR1 protein (8-10), denoted ADAR1-a, the variant designated ADAR1-b possesses a deletion of 26 a...

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