词条 | Circular RNA |
释义 |
Circular RNA (or circRNA) is a type of single-stranded RNA which, unlike the better known linear RNA, forms a covalently closed continuous loop, i.e., in circular RNA the 3' and 5' ends normally present in an RNA molecule have been joined together. This feature confers numerous properties to circular RNAs, many of which have only recently been identified. Many circular RNAs arise from otherwise protein-coding genes. They have been categorized as noncoding RNA, but more recently, they have been shown to code for proteins.[1][2] Some circular RNAs have recently shown potential as gene regulators. Like many other alternative noncoding isoforms, the biological function of most circular RNAs are unclear. Because circular RNAs do not have 5' or 3' ends, they are resistant to exonuclease-mediated degradation and are presumably more stable than most linear RNAs in cells.[3] RNA splicingIn contrast to genes in bacteria, eukaryotic genes are split by non-coding sequences known as introns. In eukaryotes, as a gene is transcribed from DNA into a messenger RNA (mRNA) transcript, intervening introns are removed, leaving only exons in the mature mRNA, which can subsequently be translated to produce the protein product.[4] The spliceosome,[4] a protein-RNA complex located in the nucleus, catalyzes splicing in the following manner:
Alternative splicingAlternative splicing is a phenomenon through which one RNA transcript can yield different protein products based on which segments are considered "introns" and which are considered "exons" during each splicing event.[4] Although not specific for humans, it is a partial explanation for the fact that human and other, much more simple species (such as nematodes) have a similar number of genes (in the range of 20 - 25 thousand).[5] One of the most striking examples of alternative splicing is in the Drosophila DSCAM gene. This single gene can give rise to approximately 30 thousand distinct alternatively spliced isoforms.[6]Non-canonical splicingExon scramblingExon scrambling, also called exon shuffling, describes an event in which exons are spliced in a "non-canonical" (atypical) order. There are three ways in which exon scrambling can occur:
The notion that circularized transcripts are byproducts from imperfect splicing is supported by the low abundance and the lack of sequence conservation of most circRNAs,[11] but has recently been challenged.[7][8][9] Characteristics of circular RNA{{prose|section|date=February 2016}}Genome-wide identification of circRNAsSeveral research groups have characterized circular RNAs by sorting through vast collections of RNA sequencing data.[7][10][9][11][12] Since circRNAs are non-polyadenylated, poly(A)-selected RNA-seq data cannot be used for circRNA discovery. To identify potential circular RNA isoforms, one typically searches for sequencing reads showing a junction between two "scrambled" exons. A brief summary of each group's results follows: Salzman et al. 2012[7]
Jeck et al. 2013[9]
Memczak et al. 2013[11]
Guo et al. 2014[10]
Length of circRNAsA recent study of human circRNAs revealed that these molecules are usually composed of 1–5 exons.[11] Each of these exons can be up to 3x longer than the average expressed exon,[9] suggesting that exon length may play a role in deciding which exons to circularize. 85% of circularized exons overlap with exons that code for protein,[11] although the circular RNAs themselves do not appear to be translated. During circRNA formation, exon 2 is often the upstream "acceptor" exon.[7] Introns surrounding exons that are selected to be circularized are, on average, up to 3x longer than those not flanking pre-circle exons,[7][9] although it is not yet clear why this is the case. Compared to regions not resulting in circles, these introns are much more likely to contain complementary inverted Alu repeats; Alu is the most common transposon in the genome.[9] By the Alu repeats base pairing to one another, it has been proposed that this may enable the splice sites to find each other, thus facilitating circularization.[8][9] Introns within the circRNAs are retained at a relatively high frequency (~25%),[10] thus adding extra sequence to the mature circRNAs. Location of circRNAs in the cellIn the cell, circRNAs are predominantly found in the cytoplasm, where the number of circular RNA transcripts derived from a gene can be up to ten times greater than the number of associated linear RNAs generated from that locus. It is unclear how circular RNAs exit the nucleus through a relatively small nuclear pore. Because the nuclear envelope breaks down during mitosis, one hypothesis is that the molecules exit the nucleus during this phase of the cell cycle.[9] However, certain circRNAs, such as CiRS-7/CDR1as, are expressed in neuronal tissues,[11][14] where mitotic division is not prevalent. CircRNAs are stable compared to linear RNAsCircRNAs lack polyadenylated tail and therefore are predicted to be less prone to degradation by exonucleases. In 2015, Enuka et al. measured the half-lives of 60 circRNAs and their linear counterparts expressed from the same host gene and revealed that the median half-life of circRNAs of mammary cells (18.8–23.7 h) is at least 2.5 times longer than the median half-life of their linear counterparts (4.0–7.4 h).[15] Generally, the lifetime of RNA molecules defines their response time.[16] Accordingly, it was reported that mammary circRNAs respond slowly to stimulation by growth factors.[15] Plausible functions of circular RNAEvolutionary conservation of circularization mechanisms and signalsCircRNAs have been identified in various species across the domains of life. In 2011, Danan et al. sequenced RNA from Archaea. After digesting total RNA with RNase R, they were able to identify circular species, indicating that circRNAs are not specific to eukaryotes.[17] However, these archaeal circular species are probably not made via splicing, suggesting that other mechanisms to generate circular RNA likely exist. In a closer evolutionary connection, a comparison of RNA from mouse testes vs. RNA from a human cell found 69 orthologous circRNAs. For example, both humans and mice encode the HIPK2 and HIPK3 genes, two paralogous kinases which produce a large amount of circRNA from one particular exon in both species.[9] Evolutionary conservation reinforces the likelihood of a relevant and significant role for RNA circularization. CDR1as/CiRS-7 as a miR-7 spongemicroRNAs (miRNAs) are small (~21nt) non-coding RNAs that repress translation of messenger RNAs involved in a large, diverse set of biological processes.[18] They directly base-pair to target messenger RNAs (mRNAs), and can trigger cleavage of the mRNA depending on the degree of complementarity. MicroRNAs are grouped in "seed families." Family members share nucleotides #2–7, called the seed region.[19] Argonaute proteins are the "effector proteins" which help miRNAs carry out their job, while microRNA sponges are RNAs that "sponge up" miRNAs of a particular family, thereby serving as competitive inhibitors that suppress the ability of the miRNA to bind its mRNA targets, thanks to the presence of multiple binding sites that recognize a specific seed region.[19] Certain circular RNAs have many miRNA binding sites, which yielded a clue that they may function in sponging. Two recent papers confirmed this hypothesis by investigating a circular sponge called CDR1as/CiRS-7 in Detail, while other groups found no direct evidence for circular RNAs acting as miRNA sponges by analyzing the potential interaction of circular RNAs with the Argonaut (AGO) Protein using high-throughput sequencing of RNA isolated by cross-linking and immunoprecipitation (HITS-CLIP) data .[12] CDR1as/CiRS-7 is encoded in the genome antisense to the human CDR1 (gene) locus (hence the name CDR1as),[11] and targets miR-7 (hence the name CiRS-7 – Circular RNA Sponge for miR-7).[14] It has over 60 miR-7 binding sites, far more than any known linear miRNA sponge.[11][14] AGO2 is miR-7's associated Argonaute protein (see above). Though CDR1as/CiRS-7 can be cleaved by miR-671 and its associated Argonaute protein,[14] it cannot be cleaved by miR-7 and AGO2. MicroRNA cleavage activity depends on complementarity beyond the 12th nucleotide position; none of CiRS-7's binding sites meet this requirement. An experiment with zebrafish, which do not have the CDR1 locus in their genome, provides evidence for CiRS-7's sponge activity. During development, miR-7 is strongly expressed in the zebrafish brain. To silence miR-7 expression in zebrafish, Memczak and colleagues took advantage of a tool called morpholino, which can base pair and sequester target molecules.[20] Morpholino treatment had the same severe effect on midbrain development as ectopically expressing CiRS-7 in zebrafish brains using injected plasmids. This indicates a significant interaction between CiRS-7 and miR-7 in vivo.[11] Another notable circular miRNA sponge is SRY. SRY, which is highly expressed in murine testes, functions as a miR-138 sponge.[14][21] In the genome, SRY is flanked by long inverted repeats (IRs) over 15.5 kilobases (kb) in length. When one or both of the IRs are deleted, circularization does not occur. It was this finding that introduced the idea of inverted repeats enabling circularization.[22] Because circular RNA sponges are characterized by high expression levels, stability, and a large number of miRNA binding sites, they are likely to be more effective sponges than those that are linear.[8] Other possible functions for circRNAsThough recent attention has been focused on circRNA's "sponge" functions, scientists are considering several other functional possibilities as well. For example, some areas of the mouse adult hippocampus show expression of CiRS-7 but not miR-7, suggesting that CiRS-7 may have roles that are independent of interacting with the miRNA.[11] Potential roles include the following:
Circular intronic long non-coding RNAs (ciRNAs)Usually, intronic lariats (see above) are debranched and rapidly degraded. However, a debranching failure can lead to the formation of circular intronic long non-coding RNAs, also known as ciRNAs.[25] CiRNA formation, rather than being a random process, seems to depend on the presence of specific elements near the 5' splice site and the branchpoint site (see above). CiRNAs are distinct from circRNAs in that they are prominently found in the nucleus rather than the cytoplasm. In addition, these molecules contain few (if any) miRNA binding sites. Instead of acting as sponges, ciRNAs seem to function in regulating the expression of their parent genes. For example, a relatively abundant ciRNA called ci-ankrd52 positively regulates Pol II transcription. Many ciRNAs remain at their "sites of synthesis" in the nucleus. However, ciRNA may have roles other than simply regulating their parent genes, as ciRNAs do localize to additional sites in the nucleus other than their "sites of synthesis".[25] Circular RNA and diseaseAs with most topics in molecular biology, it is important to consider how circular RNA can be used as a tool to help mankind. Given its (1) abundance, (2) evolutionary conservation, and (3) potential regulatory role, it is worthwhile to look into how circular RNA can be used to study pathogenesis and devise therapeutic interventions. For example:
Viroids as circular RNAs{{main|Viroid}}Viroids are mostly plant pathogens, which consist of short stretches (a few hundred nucleobases) of highly complementary, circular, single-stranded, and non-coding RNAs without a protein coat. Compared with other infectious plant pathogens, viroids are extremely small in size, ranging from 246 to 467 nucleobases; they thus consist of fewer than 10,000 atoms. In comparison, the genome of the smallest known viruses capable of causing an infection by themselves are around 2,000 nucleobases long.[27] DatabasesRecently were created various circRNA databases for the identification and study of this kind of RNAs. See also
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