出典(authority):フリー百科事典『ウィキペディア(Wikipedia)』「2012/07/27 12:50:59」(JST)
The term RNA editing describes those molecular processes in which the information content in an RNA molecule is altered through a chemical change in the base makeup. To date, such changes have been observed in tRNA, rRNA, mRNA and microRNA molecules of eukaryotes but not prokaryotes. RNA editing occurs in the cell nucleus and cytosol, as well as in mitochondria and plastids, which are thought to have evolved from prokaryotic-like endosymbionts.
Most of the RNA-editing processes, however, appear to be evolutionarily recent acquisitions that arose independently. The diversity of RNA editing phenomena includes nucleoside modifications such as cytidine (C) to uridine (U) and adenosine (A) to inosine (I) deaminations, as well as non-templated nucleotide additions and insertions. RNA editing in mRNAs effectively alters the amino acid sequence of the encoded protein so that it differs from that predicted by the genomic DNA sequence.[1]
Contents
|
RNA editing through the addition and deletion of uracil has been found in kinetoplasts from the mitochondria of Trypanosoma brucei[2] Because this may involve a large fraction of the sites in a gene, it is sometimes called "pan-editing" to distinguish it from topical editing of one or a few sites.
Pan-editing starts with the base-pairing of the unedited primary transcript with a guide RNA (gRNA), which contains complementary sequences to the regions around the insertion/deletion points. The newly formed double-stranded region is then enveloped by an editosome, a large multi-protein complex that catalyzes the editing.[3][4] The editosome opens the transcript at the first mismatched nucleotide and starts inserting uridines. The inserted uridines will base-pair with the guide RNA, and insertion will continue as long as A or G is present in the guide RNA and will stop when a C or U is encountered.[5][6] The inserted nucleotides cause a frameshift and result in a translated protein that differs from its gene.
The mechanism of the editosome involves an endonucleolytic cut at the mismatch point between the guide RNA and the unedited transcript. The next step is catalyzed by one of the enzymes in the complex, a terminal U-transferase, which adds Us from UTP at the 3’ end of the mRNA.[7] The opened ends are held in place by other proteins in the complex. Another enzyme, a U-specific exoribonuclease, removes the unpaired Us. After editing has made mRNA complementary to gRNA, an RNA ligase rejoins the ends of the edited mRNA transcript.[8][9] As a consequence, the editosome can edit only in a 3’ to 5’ direction along the primary RNA transcript. The complex can act on only a single guide RNA at a time. Therefore, a RNA transcript requiring extensive editing will need more than one guide RNA and editosome complex.
The editing involves cytidine deaminase that deaminates a cytidine base into a uridine base. An example of C-to-U editing is with the apolipoprotein B gene in humans. Apo B100 is expressed in the liver and apo B48 is expressed in the intestines. The B100 form has a CAA sequence that is edited to UAA, a stop codon, in the intestines. It is unedited in the liver.
A-to-I editing occurs in regions of double-stranded RNA (dsRNA). Adenosine deaminases acting on RNA (ADARs) are the RNA-editing enzymes involved in the hydrolytic deamination of Adenosine to Inosine (A-to-I editing). A-to-I editing can be specific (a single adenosine is edited within the stretch of dsRNA) or promiscuous (up to 50% of the adenosines are edited). Specific editing occurs within short duplexes (e.g., those formed in an mRNA where intronic sequence base pairs with a complementary exonic sequence), while promiscuous editing occurs within longer regions of duplex (e.g., pre- or pri-miRNAs, duplexes arising from transgene or viral expression, duplexes arising from paired repetitive elements). There are many effects of A-to-I editing, arising from the fact that I behaves as if it is G both in translation and when forming secondary structures. These effects include alteration of coding capacity,[10] altered miRNA or siRNA target populations, heterochromatin formation, nuclear sequestration, cytoplasmic sequestration, endonucleolytic cleavage by Tudor-SN, inhibition of miRNA and siRNA processing,and altered splicing.
It has been shown in previous studies that the only types of RNA editing seen in the plants’ mitochondria and plastids are conversion of C to U and U to C (very rare) [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] .[23] RNA-editing sites are found mainly in the coding regions of mRNA, introns, and other non-translated regions.[13] In fact, RNA editing can restore the functionality of tRNA molecules.[15][16] The editing sites are found primarily upstream of mitochondrial or plastid RNAs[39]. The exact mechanism is unknown, but previous studies have speculated the involvement of gRNA and the editosome complex. The reason behind that specific idea arose from the fact that there are too many editing sites that needed to be changed in those organelles for a deaminase.
RNA editing is essential for the normal functioning of the plant’s translation and respiration activity [24] It has also been linked to the production of RNA-edited proteins that are incorporated into the polypeptide complexes of the respiration pathway. Therefore, it is highly probable that polypeptides synthesized from unedited RNAs would not function properly and hinder the activity of both mitochondria and plastids.
RNA editing in viruses (i.e., measles, mumps, or parainfluenza) are used for stability and generation of protein variants [25] [26] . Viral RNAs are transcribed by a virus-encoded RNA-dependent RNA polymerase, which is prone to pausing and “stuttering” at certain nucleotide combinations. In addition, up to several hundred non-templated As are added by the polymerase at the 3’ end of nascent mRNA.[27] These As help stabilize the mRNA. Furthermore, the pausing and stuttering of the RNA polymerase allows the incorporation of one or two Gs or As upstream of the translational codon.[27] The addition of the non-templated nucleotides shifts the reading frame, which generates a different protein.
The RNA-editing system seen in the animal may have evolved from mononucleotide deaminases, which have led to larger gene families that include the apobec-1 and adar genes. These genes share close identity with the bacterial deaminases involved in nucleotide metabolism. The adenosine deaminase of E. coli cannot deaminate a nucleoside in the RNA; the enzyme’s reaction pocket is too small to for the RNA strand to bind to. However, this active site is widened by amino acid changes in the corresponding human analog genes, APOBEC-1 and ADAR, allowing deamination [28] .[29] The gRNA-mediated pan-editing in trypanosome mitochondria, involving templated insertion of U residues, is an entirely different biochemical reaction. The enzymes involved have been shown in other studies to be recruited and adapted from different sources.[3][30] But, the specificity of nucleotide insertion via the interaction between the gRNA and mRNA are similar to the tRNA editing processes in the animal and Acanthamoeba mithochondria.[31] Eukaryotic ribose methylation of rRNAs by guide RNA molecules is a similar form of modification.[32]
Thus, RNA editing evolved more than once. Several adaptive rationales for editing have been suggested (references in.[33] Editing is often described as a mechanism of correction or repair to compensate for defects in gene sequences. However, in the case of gRNA-mediated editing, this explanation does not seem possible because if a defect happens first, there is no way to generate an error-free gRNA-encoding region, which presumably arises by duplication of the original gene region. This thinking leads to an entirely different evolutionary proposal (called "constructive neutral evolution" in [34]) in which the order of steps is reversed, with the gratuitous capacity for editing preceding the "defect" [34] 31
A recent study looked at the involvement of RNA editing in RNA degradation.[35] The researchers specifically looked at the interaction between ADAR1 and hUpf1, an enzyme involved in the nonsense-mediated mRNA decay pathway(NMD). They found that ADAR1 and hUpf1 are found within the suprasliceosome and they form a complex that lead to the down-regulation of specific genes. The exact mechanism or the exact pathways that these two are involved in are unknown at this time. The only fact that this research has shown is that they form a complex and down-regulate specific genes.
|
全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.
リンク元 | 「RNAエディティング」 |
関連記事 | 「R」「RNA」「editing」 |
.