RNA editing in plants and its evolution.

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Annu. Rev. Genet. 2013.47:335-352. Downloaded from www.annualreviews.org by New York University - Bobst Library on 11/28/13. For personal use only.

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RNA Editing in Plants and Its Evolution Mizuki Takenaka, Anja Zehrmann, Daniil Verbitskiy, Barbara Härtel, and Axel Brennicke Molekulare Botanik, Universität Ulm, 89069 Ulm, Germany; email: [email protected], [email protected], [email protected], [email protected], [email protected]

Annu. Rev. Genet. 2013. 47:335–52 The Annual Review of Genetics is online at genet.annualreviews.org This article’s doi: 10.1146/annurev-genet-111212-133519 c 2013 by Annual Reviews. Copyright All rights reserved

Keywords mitochondria, plastids, PPR proteins, MORF proteins, cytidine deamination, RNA-protein interaction

Abstract RNA editing alters the identity of nucleotides in RNA molecules such that the information for a protein in the mRNA differs from the prediction of the genomic DNA. In chloroplasts and mitochondria of flowering plants, RNA editing changes C nucleotides to U nucleotides; in ferns and mosses, it also changes U to C. The approximately 500 editing sites in mitochondria and 40 editing sites in plastids of flowering plants are individually addressed by specific proteins, genes for which are amplified in plant species with organellar RNA editing. These proteins contain repeat elements that bind to cognate RNA sequence motifs just 5 to the edited nucleotide. In flowering plants, the site-specific proteins interact selectively with individual members of a different, smaller family of proteins. These latter proteins may be connectors between the site-specific proteins and the as yet unknown deaminating enzymatic activity.

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INTRODUCTION


RNA editing: posttranscriptional modification of RNA that changes the information content

The term RNA editing describes processes that alter the identity of nucleotides in RNA molecules or that add or delete nucleotides so that the information in the mature RNA differs from that defined in the genome. Diverse processes of RNA editing are found in viruses, primitive eukaryotes, vertebrates, fungi, and plants. RNA-editing processes are used as control checkpoints, can restore the function of the encoded protein, and can create different proteins. Excellent reviews of the various processes in different organisms have recently appeared and describe their mechanistic and functional aspects and their origins (1, 23, 40, 56, 64, 88). Here, we focus on the RNA-editing process in land plants in which this is an essential step of RNA maturation in the two organelles with resident genomes: mitochondria and plastids (14, 21, 37, 70).

RNA EDITING IN PLANTS In flowering plants (angiosperms), RNA editing was first recognized in mitochondria in 1989 as sequence differences between DNA and RNA (16, 27, 32). These differences of U nucleotides in the RNA in positions of C nucleotides in the DNA were found to be caused by substitutional C-to-U changes in the RNA (Figure 1a). The amino acid codons specified after editing are more similar to those present at the respective positions of orthologous proteins in other organisms. Three years later, the same type of RNA editing involving C-to-U changes was also documented in plastids (33). Editing in both organelles was subsequently reported in all land plants, including all major plant lineages from the bryophytes to gymnosperms and in all angiosperms (73, 74, 78, 91). The notable exceptions are some species of liverworts in the branch of the Marchantiales, in which the messenger RNAs (mRNAs) remain as specified by the genomes in plastids as well as in mitochondria (Figure 1b) (66). At present, no RNA editing has been observed in cytoplasmic RNAs of plants. The process seems to be confined to the two organelles. 336

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Another species-specific feature is the distribution of the U-to-C reverse reaction RNA editing, which occurs only in ferns, mosses, and Lycopodiaceae in addition to many C-toU changes (Figure 1b) (24, 42). In flowering plants, posttranscriptional mRNA editing is performed generally as C-to-U alterations of nucleotide identity (22). Most of the RNA-editing events occur at the first or second positions of codons and thus usually alter the codon given in the genome and transcribed into the precursor mRNA (premRNA) (Figure 1a). Consequently, the mature RNA specifies a different amino acid than that encoded by the genomic DNA. To predict the final protein sequence synthesized from a given gene, it is therefore not sufficient to determine the genomic sequence because only the mature mRNA sequence contains this information. The C-to-U RNA editing can alter any codon containing a C nucleotide, including the generation of initiation codons by changing ACG to AUG and the introduction of translation termination signals by changing CGA to UGA or CAA to UAA. Conversely, the U-toC RNA editing found in mosses and ferns can convert translational stop codons, such as UAA termination signals, to a CAA triplet coding for the amino acid glycine. The final open reading frames can thus not only become different from those originally encoded by the genome but can also be extended or shortened. RNA editing in plant organelles is a posttranscriptional process. The competence of lysates from mitochondria or plastids to faithfully edit an in vitro synthesized and added RNA molecule shows that this editing does not depend on a close link to the transcription machinery (7, 30, 55, 63, 76, 84, 85). However, only a few sites can be edited in vitro, suggesting that often the editing activity may require a complex machinery of several proteins that is not readily assembled on in vitro–added RNA molecules. The C-to-U and the U-to-C types of RNA editing occur in plastids and in plant mitochondria in not only mRNAs but also in transfer RNAs (tRNAs), introns, and 5 - and

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Figure 1 Plant organellar RNA editing alters nucleotide identities in almost all land plants. (a) The C-to-U alteration can change amino acid codons and introduce translational start and stop codons. This results in different amino acids being incorporated into the mature RNA than were predicted from the genomic DNA. Plants shown in the photographs are from left to right: the liverwort Marchantia polymorpha, a representative fern, and two angiosperms (flowering plants). (b) In all land plant lineages, RNA editing changes C nucleotide identities to U in mitochondria and plastids. In green algae, no editing has been reported to date. In the branch of the liverworts that contains the species Marchantia polymorpha, editing has been lost secondarily. Numbers of editing sites are given for species in which the full complement has been analyzed. In some species, extensive editing has been reported, although the full extent still needs to be determined.

3 -untranslated sequences (6, 12, 24, 49). In ribosomal RNAs, editing appears to be absent or very infrequent. The reason for this suppression of editing can only be speculated; it may be connected to a rapid compartmentalization of the rRNAs by protein coverage. In introns, editing seems to be required in some instances for efficient splicing. In tRNAs, editing events can be required for processing of precursor RNA molecules (6). However, in both

organelles, RNA editing is most prevalent in the coding regions of mRNAs. The amino acids specified by the codons generated by editing in the mRNA are generally better conserved in evolution than the amino acids encoded by the genomic DNA (27). This observation suggests that RNA editing in plants restores codons altered by mutation to (again) encode the amino acids that are optimal or even required for function of the respective protein. RNA editing can www.annualreviews.org • RNA Editing in Plants

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then be considered to act as an indirect repair mechanism that corrects DNA mutations on the RNA level.

PPR proteins: pentatricopeptide repeat proteins

THE RNA: CIS ELEMENTS


The nucleotide to be edited must be recognized and targeted within the multitude of C nucleotides in the population of RNA molecules. In recent years, in vivo [trans-plastidic (9–11, 47)], in vitro (55, 84, 85), and in organello (7, 19, 36) investigations have identified the crucial cis elements in the polynucleotide RNA chain for a number of editing sites. There is no common denominator distinguishing a C to be edited from an unedited C, implying that editing sites are addressed individually through a unique sequence pattern. In all instances, stretches of 20 to 25 nucleotides in the RNA mostly upstream (5 ) of the editing site provide a specific sequence context that is recognized by the editing activity (9, 15, 85). When mutations of these sequence regions from several editing sites were tested in in vitro and in organello assays, the crucial nucleotides were found to reside in a window between 5 and 15 nucleotides upstream of the edited C (9, 15, 19, 36, 55, 84, 85). The gap to the edited C suggests that the site-specific trans-factors do not actually discriminate the nucleotides adjacent to the edited nucleotide. Mechanistically, either the site-specific factors stretch across this gap or one or more other proteins are recruited for the deamination reaction. Such spatial constraints may also be responsible in selecting the nucleotide identity just upstream of the edited C. At this −1 position, G and A nucleotides are highly underrepresented and can be found only at a very few editing sites (22). In some instances, nucleotide identities farther from this central motif appear to influence attachment of the respective specificity factors (85). Nucleotides more than 30 moieties upstream from the edited C or closer to this position and even downstream in the mRNA influence RNA editing in vitro. These very variable parameters suggest that individual recognition patterns are used at each site, further support338

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ing the inference that different trans-factors are involved at different editing events. Indeed, several site-specific trans-factors have been identified in recent years that confirm that the unique RNA sequence motifs upstream of editing sites are individually recognized by specific proteins encoded in the nuclear genome.

THE PROTEINS: TRANS-FACTORS Pentatricopeptide Repeat Proteins Are the Specificity Factors The first such trans-factor was identified in 2005 for an RNA-editing event in plastids by tracing a rather unspecific mutant phenotype to the nuclear gene responsible (41). The physiological defect identified as a disturbed function of the plastid NADH dehydrogenase is caused by a single RNA-editing defect in the RNA for a specific subunit of this protein complex. The affected editing event creates an AUG translational start from the genomic ACG codon. Consequently, without this editing event, the NADH dehydrogenase subunit protein is not synthesized and the complex cannot be functionally assembled in the mutant of the RNA-editing specificity factor. Analysis of other mutants incapacitated in various plastid functions led to further similar proteins, all of them uniquely addressing one or a very few editing sites in plastid mRNAs (29, 44, 57, 59). The first factor for editing events in mitochondrial mRNAs was identified by genomic mapping of ecotype-specific editing variants and tracing these to the altered genes (93). More recently, a direct screening approach has been developed to identify specific RNAediting aberrations in a randomly mutated plant population and to trace the respective mutation to an individual plant and therein to the gene affected (28, 75, 77, 86, 87, 93). The nuclear-encoded factors required for editing of one to as many as eight to ten sites in mitochondria and plastids belong to the family of the pentatricopeptide repeat (PPR) proteins. This protein family is specifically amplified in


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plants, whereas the nuclear genomes of fungi, protists, and animals code for only few members of this class of proteins (2, 38, 46, 57, 58, 60, 69, 71). Almost all of the PPR proteins are targeted to mitochondria or plastids (the two organelles with genomes), where they are involved in various RNA-processing steps, including intron splicing, endonucleolytic processing, RNA stability, and access to translation. The RNA-editing factors in plants belong to an approximately 200-member-strong subgroup of the PPR proteins, which is characterized by a mixture of 35-mer amino acid repeats (P) and PPR repeats that are slightly longer (L), with as many as 37 amino acids, or shorter (S), with 31 to 34 amino acids (46, 69, 71). At their C termini, following the last PPR motif, these RNA-editing proteins are extended by an E (extension) domain. The E region displays some features of PPR elements, suggesting that such an element was part of the E-domain ancestor and that some properties may have been retained (Figure 2). About half of the E-type PPR proteins are further extended by an approximately 100-amino-acid-long DYW region. This element is named after the three highly conserved C-terminal amino acids: aspartic acid (D), tyrosine (Y), and tryptophan (W) (Figure 2). The DYW region is essential in some of the DYW PPR proteins but is not required for functional activity in others, at least in complementation assays of mutants (17, 57). One protein in Arabidopsis, DYW1, consists of a well-conserved DYW domain and of a region with rudimentary similarity to a partial E domain (Figure 2) (13). The DYW1 protein interacts in plastids with the first identified RNA-editing specificity factor CRR4, which lacks a DYW region, to edit the ACG codon to an AUG. Both proteins are required here, suggesting that a DYW domain is essential but may be provided in trans if not present in cis on the PPR editing factor. The nuclear genome of Arabidopsis thaliana codes for 194 E-type PPR proteins. Six additional genes code for PPR proteins that consist of the PLS repeat elements that are characteristic for this subgroup but do not encompass

an E domain. These approximately 200 proteins are not enough to individually specify the 450–500 editing sites in mitochondria and plastids. Indeed, many of these proteins are found to target several sites. Although several of the assigned RNA-editing PPR proteins appear to address individual sites, some are required for as many as six or even eight editing events. Surprisingly, the common targets of a given PPR protein sometimes show very little sequence similarity in their cis elements upstream of the edited nucleotides, suggesting that different nucleotide combinations may confer recognition and binding of the same PPR protein (79). In some instances, such flexible connections between the PPR proteins and the RNA sequence lead to overlapping specificities, resulting in two PPR proteins able to target the same editing site. Evidence for such redundancies is mostly indirect from those cases in which a complete knockout of one PPR protein only reduces editing at a given site but does not lead to a complete loss of the nucleotide conversion (93). At these sites, another PPR protein presumably must be able to provide the residual activity, albeit less efficiently. Direct evidence has so far been reported for the two rather similar PPR proteins MEF8 and MEF8S (87). The acronym MEF designates the PPR proteins identified as mitochondrial RNA-editing factors. The target sites of MEF8 and MEF8S seem to be identical, and the editing levels at the sites are directly correlated with the expression pattern of the resident intact PPR protein in a knockout plant of the respective other protein. The overlapping specificities and target sequences of different RNA-editing PPR proteins have consequences for our view of the specificity of the RNA-PPR interaction. There may actually be a large number of such redundancies and hidden targets, which could imply a more degenerate and flexible RNA-PPR code interaction.

E (extension) domain: the extension domain evolved from an ancient PPR element; only found in RNA-editing PPR proteins DYW domain: another extension beyond the E domain with signature amino acids of cytidine deaminases and containing the three highly conserved amino acids D (aspartic acid), Y (tyrosine), and W (tryptophan) at the C terminus PLS repeats: PPR repeats that consist of P (normal PPR), L (longer PPR), and S (shorter PPR) motifs. This pattern is generally present in PPR-type RNA-editing factors in plant organelles

The PPR Protein to RNA Code RNA binding of PPR proteins has been shown for several RNA-editing proteins but www.annualreviews.org • RNA Editing in Plants

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Figure 2 Structure of pentatricopeptide repeat (PPR) proteins involved in plant organellar RNA editing. The proteins that recognize a specific RNA sequence just upstream of an RNA-editing site belong to the superfamily of PPR proteins. Aligned here are several representative editing factors from plastids (cp; CRR22, CLB19, and CRR4) and mitochondria (mt; MEF11, MEF21, and MEF19). These examples display the principle of the structure and the variations in the numbers of the three different types of repeats (S, small; P, medium sized; L, long repeats). The RNA-editing subfamily of the PPR proteins is characterized by a modular structure within which each of the PLS repeats presumably contacts one nucleotide. The function of the extension (E) domain is not yet clear, and the optional C-terminal DYW domain may provide deaminase activity for the C-to-U nucleotide conversion in the RNA. In both compartments, proteins with a DYW domain and few if any PPR elements can be found. As examples, DYW1 in plastids and MEF8 in mitochondria are depicted. All RNA-editing PPR proteins in the moss Physcomitrella patens contain E and DYW domains. On the left of the respective protein structure, the N-terminal elements labeled cp or mt denote the predicted respective target sequences. The N-terminal part of the MEF8 E domain shows relatively low similarity to other E domains (light green).

is most intensively documented for PPR proteins involved in other RNA-processing reactions (59, 69, 90). For PPR proteins protecting against endo- or exonucleases, tight contact to the RNA is expected and indeed found to be very sequence specific. However, RNA-editing PPR proteins are expected to bind reversibly because the mature RNA 340

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needs to be readily accessible to the ribosome for protein synthesis. Nevertheless, attachment of some PPR proteins to their specific RNA targets has been observed in several instances. The main problem encountered with these assays is the difficulty of obtaining PPR proteins by expression of their coding sequences (20) in bacterial cells. In bacteria,


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the PPR proteins are synthesized but usually aggregate or are sequestered into inclusion bodies and are not soluble. This holds true for the expression of single PPR repeats as well as for the E and DYW domains without any repeat. Although no direct structural data of the PPR proteins could be obtained, predictions of their 3D structures generally suggest two helical structures within each repeat unit (20, 39, 53, 69, 71). Starting from the presumption that each repeat attaches to one nucleotide in the RNA, amino acid coincidences with nucleotide identities in the target RNA can be calculated. These presumptions seem to be valid, given that the parameters identified through such alignments yield reasonably accurate computational correlation tools, which have been used to correctly predict the target sites for previously unassigned RNA-editing PPR proteins (3, 29, 39, 53, 80). These assignments even allow the intelligent manipulation of the RNA target sites to eventually generate PPR proteins, which can be designed to bind to any given RNA sequence. This fact has been proven in assays of PPR proteins in which only the crucial nucleotide determinator amino acid identities were altered. The recoded PPR proteins bind specifically to the correspondingly altered RNA sequence (3). Such designed RNA-binding proteins complement the DNAbinding TAL proteins, which likewise use a 34-mer–amino acid repeat structure to define a specific sequence pattern as a target for binding in double-stranded DNA nucleotide polymers (8).

Multiple Site-Specific Proteins: Multiple Organellar RNA-Editing Factors Along with the RNA sequence-specific PPR proteins, another group of proteins is required for RNA editing at all sites in flowering plant mitochondria as well as plastids (Figure 3). In the genome of Arabidopsis, ten members of this small family of proteins are encoded; two are targeted to plastids and five or six are targeted to mitochondria, with one or two possibly im-

ported into both organelles (5, 81). One protein contains only half of the only conserved region and may be a pseudogene. These proteins are each required for numerous editing sites and have been designated accordingly as multiple organellar RNA-editing factors (MORFs) (81). Mutation of one such MORF results in loss of RNA editing at several sites and reduction of editing at many sites. In the plastid, mutation of either of the two MORFs targeted exclusively to this compartment affects almost all editing sites, suggesting that both proteins are involved in editing at a given site. At some sites, editing is completely lost when only one of the two factors is absent (81). Both plastid MORF proteins are therefore predicted to form homomers and heteromers, implying that they may, in some instances, be able to provide their function in editing as homomers. At other sites heteromers may be required, but at most of the editing sites either the homomer or heteromer seems to be functional, although the heteromers appear to be more prevalent. This inference is suggested by the reduced editing observed at most of the plastid editing sites when either of the two MORFs is missing (81). The actual function of the MORF proteins in the hypothetical editosome in plastids and mitochondria is as yet unknown. Because they show no similarity to known functional protein domains (specifically, they do not carry any cytidine deaminase signatures), they may provide a function as connectors between the RNA-binding PPR proteins and the actual enzymatic activity (Figure 4). This notion is supported by the observation that MORF proteins can interact with the PPR proteins involved in RNA editing. The mitochondrial MORF proteins discriminate between different PPR proteins in yeast two-hybrid assays (81). In some instances, the MORF protein required for editing a given site indeed interacts with the specific PPR protein, which is also essential for processing this site. The MORF proteins may be involved in bridging the distance of four nucleotides between the nucleotides contacted by the PPR proteins and the actually edited C moiety to guide the enzyme. www.annualreviews.org • RNA Editing in Plants

Multiple organellar RNA-editing factors (MORF) proteins: individual MORF proteins are involved in RNA editing at numerous sites in flowering plants Editosome: the hypothetical protein complex that associates with mitochondrial or plastid RNA to alter a C or U nucleotide to the respective other identity

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Figure 3 Multiple organellar RNA-editing factor (MORF) proteins are required for RNA editing in plastids and mitochondria of flowering plants in addition to the pentatricopeptide repeat (PPR) proteins. The small family of MORF proteins is only found in flowering plants, suggesting these are a recent addition to the RNA-editing process. In Arabidopsis thaliana, nine genes encode proteins with full-length conserved central domains; MORF10 contains only part of this region. Two of the nine full-length genes are specific for the plastid (MORF2 and MORF9; shaded green), MORF8 is dual targeted to both organelles, and the other MORFs are specific to mitochondria. This unrooted tree visualizes the species-specific variation of genes for MORF proteins between the flowering plants rice (Oryza), poplar (Populus), grape (Vitis), and thale cress (Arabidopsis). This suggests that similar species-specific MORF proteins are recent derivates and may at least partially substitute for each other. Different numbers of genes for MORF proteins are encoded in other flowering plant species. MORFs are not found in nonflowering plants. 342

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Figure 4 Model of the presently identified composition of the hypothetical editosome in flowering plant organelles. A pentatricopeptide repeat (PPR) protein binds to a specific combination of nucleotides in the RNA. One or more multiple organellar RNA-editing factor (MORF) proteins interact with the PPR protein and attract the enzymatic activity. This most likely deaminase activity may be a DYW domain from a respective (second) PPR protein or an entirely different moiety. Bullets represent nucleotides in the RNA. Cartridges in the PPR proteins denote the degenerate repeats of approximately 35 amino acids. The E and DYW domains of the respective PPR proteins are indicated.

The only discernible feature present in all nine members of the MORF family is the so-called MORF box, which is centrally located in most MORF proteins. The function of this conserved MORF box domain is unknown; it may be a point of contact to the PPR proteins (5, 81).

The Enzyme The enzyme catalyzing the actual C-to-U conversion reaction for RNA editing in plant mitochondria and plastids has not yet been identified. So far, several conditions have been characterized that are only partially compatible with either of the classic deamination or transamination reactions. Functional in vitro assays and the absence of any in vivo intermediates with termini at editing sites suggest that the sugar-phosphate backbone remains intact during editing (7, 30, 31, 76). The C nucleotide is not excised and substituted by a U, but the C is modified in place in the RNA chain. This conclusion is supported by in vitro assays that show that an α-phosphate-labeled cytosine integrated in a substrate RNA is recovered as an α-labeled uridine (7, 63). These observations suggest that the reaction proceeds as a C-to-U deamination

step analogous to the single nucleotide conversion in the pathway of uridine and cytidine biosynthesis. Here, a classic cytidine deaminase enzyme is involved, of which seven are encoded in the Arabidopsis genome (18). However, none of them appears to be active in organellar RNA editing. Precedence for the adaptation of such a mononucleotide deaminase to be able to act on polynucleotide chains is found in the mammalian apolipoprotein C-to-U RNA editing (54). This, as well as the classic mononucleotide-specific cytidine deaminases, requires bound zinc atoms for its active center. Zinc chelators, however, do not reduce or block the plant mitochondrial activity in in vitro assays (76). Analogous assays with plastid extracts did detect an inhibition by the chelators, leaving a classic cytidine deaminase activity as a possibility (31). As a plausible alternative, it has been suggested that the PPR protein–integral DYW domains (in which the crucial amino acid patterns of classic cytidine deaminases appear to be conserved) supply the cytidine deaminase activity (67). This very attractive hypothesis implies that for editing sites recognized by E-class PPR proteins without their own DYW domain, an additional DYW class PPR protein or a protein consisting of little more than a DYW region www.annualreviews.org • RNA Editing in Plants

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is recruited. Support comes from the identification that the DYW1 protein is required together with the E-class PPR protein CRR4 for the editing at one plastid site, from the in vivo interaction of these two proteins, and from the correct function of a chimeric fusion protein of both entities (13). In most instances, PPR–PPR DYW protein interactions may be mediated by the MORF proteins, which may supply the linker between the two PPR-like proteins (Figure 4). However, a C-to-U deaminating activity of the DYW domains still needs to be shown. Yet another alternative source of the enzyme could be a modified transaminase activity. Transaminases are involved in amino acid biosynthesis pathways and require an acceptor molecule for the amino group. Several acceptor molecules known from the amino acid pathways have been tested in vitro, but none were found to influence the reaction (76). The very selective in vitro assays suggest that additional as-yet-unassigned proteins may play a role in RNA editing in plants. The positive effect of added ATP on the in vitro assays is on accessory functions rather than the reaction itself (76). The ATP enhancement implies that a step is involved that requires the energy supply. The reaction step could be traced to the release of the RNA from an attached protein, such as glutamate dehydrogenase, which is abundant in mitochondria. The protein was found to inhibit RNA editing in vitro but is specifically blocked from binding to the RNA by the presence of ATP (76). Furthermore, the ATP can be largely substituted by NTP and even dNTP, suggesting that for the RNA-editing step an RNA helicase may be activated, which unwinds and clears the target RNAs from attached nonediting proteins. All proteins involved must be identified and analyzed to understand and to eventually rebuild the plant plastid and mitochondrial editosomes in vitro.


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pendently from RNA processes in distant evolutionary lineages of animals, fungi, and protozoans when the first plants moved from the aquatic environment onto the land and developed into the ancestors of the Lycopodiaceae (21, 24, 38, 65, 73, 74, 83, 91). No editing has been observed in any alga, whereas it is prevalent in all land plants. The only exceptions are several species of the Marchantiales, which presumably lost RNA editing secondarily (25, 26, 66, 89). Within the liverwort branch, several features other than the loss of editing have changed during the evolution of the land plants. For example, the frequency of editing events per RNA unit varies greatly between different lineages. In flowering plants, 400–600 RNA-editing events occur in mitochondria, and 30–40 such alterations occur in plastids (Figure 1) (51, 62). In basal vascular plants, such as Isoetes engelmanii or Lycopodium, 1,000 to 1,500 nucleotides are altered in mitochondria (24). On the other end of the spectrum is the moss Physcomitrella patens, in which two RNA-editing events occur in plastids and eleven C nucleotides are changed to U in mitochondria (65). The number of the genes for RNA editing– type PPR proteins in a given plant species often roughly matches the number of editing sites in the organelles. The 400–500 editing sites in flowering plants are served by 200 editing-type PPR proteins; in the moss Physcomitrella, the 13 sites are recognized by 10 editing-type PPR proteins, and in the liverwort Marchantia, where no editing is observed, there are no genes for editing-type PPR proteins found in the genome. In Lycopodium, the number of editing PPR proteins is slightly increased compared with their number in flowering plants, although the number of editing sites is two to three times larger. It is possible that more sites are addressed by a single PPR protein in Lycopodium than in higher plants, or maybe the entire editing machinery has evolved differently. This scenario is a distinct option, considering that in Lycopodium no MORF proteins are encoded in the genome. Many E-type PPR proteins, which require a

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deaminase in trans and an adaptor molecule analogous to the MORF proteins, are found in the Lycopodium genome. Similarly, no genes for MORF proteins are found in Physcomitrella. In the moss and also in the protist Naegleria, this may be correlated with the presence of only DYW-domain-containing PPR proteins, but the functional significance of the coincidence will probably become apparent only after the actual contribution of the MORF proteins to the editing machinery has been clarified.

Evolution of the U-to-C-Type RNA Editing Another difference between the land plant lineages is the occurrence of the reverse RNAediting reaction, which alters a U nucleotide to a C nucleotide. This type of editing occurs in hornworts, lycopods, and ferns but is absent from liverworts, mosses, and flowering plants (24, 73, 91). This distribution suggests that this type of editing arose after the split of the mosses and the hornworts and later was lost or greatly reduced in the branch that led to the seed plants. The presence of U-to-C-type RNA editing requires a specific enzymatic activity. With only circumstantial information about the enzyme involved in the C-to-U type of reaction, two major scenarios are presently feasible. Either two distinct enzymes perform the two opposing reactions or one protein molecule catalyzes both directions of the reaction. In the first instance, the C-to-U reaction could be accelerated by a deaminase as discussed above and the amination of the U to a C could be performed by a specific enzyme adapted, for example, from the nucleotide metabolism-catabolism repertoire. The most likely precedence for the second scenario, a single enzyme for both reactions, would be a transaminase activity recruited from one of those involved in amino acid biosynthesis/degradation pathways. As outlined above, this would require an acceptor molecule on which the amino group can be deposited in the C-to-U reaction and from where the amino group could be retrieved in the U-to-C amination of the nucleotide in the

RNA. In addition, the direction of the reaction needs to be tightly controlled by accessory proteins, such as distinct types of PPR proteins.

Evolution of the Pentatricopeptide Repeat Proteins Similar to the U-to-C editing that arose during the evolution of the vascular plants and was lost in the branch that led to the flowering plant species, individual RNA-editing sites seem to appear and disappear during evolution (4, 68, 82, 92). The most striking example is the complete loss of all editing sites in the Marchantia clade of liverworts. But even between closely related species, such as Arabidopsis and Brassica, differences in individual editing sites are observed. For example, in the nad3 mRNA, site nad3-64 is edited in Arabidopsis thaliana but not in Brassica napus. This rather fast evolution of appearing and disappearing editing sites suggests that the specificity factors of editing, the PPR proteins, can mutate rapidly to alter their target restrictions. Concomitantly with the loss of an editing site by its conversion to a genomic T, the respective specificity conferring PPR protein is free to mutate or even to become lost from the nuclear genome. The remaining constraints on this PPR protein depend on its requirement for editing at other target sites. These sites may be contacted through a different set of the repeats in this PPR protein that would consequently need to be maintained. This idea may be difficult to analyze experimentally because along with the sites for which a given PPR protein is essential, there are usually other targets requiring this factor. As detailed above, these may be hidden by also being targets of other PPR proteins and therefore cannot be recognized as such in mutants of a single gene. For example, the PPR protein MEF10 is assigned to one target site in Arabidopsis, but its homolog in grape, which may or may not be an ortholog, is not required for this site because this nucleotide is already encoded as a T in the grape mitochondrial genome (28). Although this grape PPR protein is the most similar to www.annualreviews.org • RNA Editing in Plants

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MEF10 in Arabidopsis, it has accumulated so many amino acid differences in evolution that its actual function is likely to have shifted to a different editing site. At present, only one true pair of orthologous proteins has been identified, the PPR2263 protein in maize and MEF29 in Arabidopsis, which are similar in sequence and structure and target the same editing sites (72). The above example also demonstrates the rule rather than the exception in editing: RNAediting sites are necessary for optimal mitochondrial and plastid (protein) function and survival of the plant. Generally, the amino acid encoded by the edited codon is much better conserved with the respective proteins from other species. Furthermore, as in MEF10, if an editing event is lost, usually the genomic sequence has preempted the requirement for this reaction by already encoding the T at the respective position. This finding suggests that editing is important and, with the sum of its many sites, required for the plant. Direct evidence for the requirement of editing at individual sites is seen in mitochondria when homozygous knockout plants of respective PPR proteins are not viable and is seen in plastids when such mutants can grow only on sugarsupplementing media. Although in many instances the knockout mutation of a given PPR protein and the consequential loss of this editing event have no detectable phenotype in the greenhouse, their true positive value may only become apparent in the competitive native environment. Many of these editing events without any overt effect in the pampered conditions of the greenhouse may be crucial under certain environmental challenges. In particular, the loss of editing reactions at several sites in mitochondria produce pleiotropic phenotypes that are often connected to altered responses and even to survival under various stress conditions, such as drought or salt challenges (29, 44, 72, 94). Whether this is a secondary effect or whether RNA editing can be regulated to adapt the physiological response of the plant still needs to be investigated (35, 43, 50, 52).


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Selection and Maintenance of RNA-Editing Sites The general if small advantage of individual editing events also becomes apparent by the inferred selection pressure on the persistence of these sites. Such a positive selective force can be postulated from the observation that most editing events occur in coding regions and in positions where RNA editing changes codon identities. In addition, editing events in silent codon positions tend to be edited in only some molecules in the steady-state organellar mRNA population. The partial conversion of such presumably neutral sites suggests that these may be side effects of PPR proteins primarily acting at other sites. This fact and the nonrandom distribution of edited nucleotides suggest that a selective pressure acts on nonsilent sites to maintain their editing. Similar positive selection seems to apply to RNA-editing events in introns that most frequently occur in domains V and VI of the conserved group II intron structures. These are the best-conserved regions and are essential for the splicing reaction. Their secondary and tertiary structures can only fold properly after editing in some instances, and when inserted into yeast introns, only the edited intron version promotes splicing (12). In tRNAs, editing events are required for proper folding of the tRNA 3D structure, and processing of the tRNA from its respective precursor RNA is compromised before editing has occurred at some sites. However, RNA editing is not necessarily the first processing step. Intron splicing, mRNA end-trimming, and RNA editing can occur in various orders; some sites near exon borders are edited only after splicing of the nearby intron (6, 49). The examples of editing required for other processing steps prompt speculation about a potential regulatory function of RNA editing in controlling the available pool of mature functional RNA molecules. In mRNAs, this could be achieved most economically through the control of an AUG translation initiation codon from an ACG triplet. This


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change is observed in a single plastid mRNA and in a single mitochondrial mRNA. The affected plastid mRNA codes for the NdhD subunit of the NADH dehydrogenase, a protein complex that improves the efficiency of photosynthesis but is not essential for survival of the plant. In mitochondria, an AUG translational start codon is generated in the nad1 mRNA coding for a subunit of the respiratory chain NADH dehydrogenase. Editing events that create AUG codons, that help to fold introns and tRNAs, and that remove translational stops in ferns and Lycopodium may be employed in regulatory functions. At other sites, partial or slow RNA editing may create protein variants for optimal functions in different physiological requirements (45, 61). Considering the most likely evolutionary order of events, these regulatory effects are likely to have been secondarily recruited.

ORIGIN OF EDITING: SPECULATIONS The potential sense of RNA editing in terms of a payoff for the plant has been debated without a clear outcome. Any such interpretation and justification requires the framework of the origin of this editing process and the questions of why it was started and how it was initially established. Most likely, this process started by mutation of an enzyme able to perform the deamination or transamination reaction (34, 48). With this ability established, thymidine nucleotides in the genome could be substituted by cytidines with the information content being corrected in the RNA. The number of editing sites increased up to the present-day numbers with the amplification of the site-specific PPR proteins. This amplification is possibly limited by the burden of eventually carrying an excess of genes for the PPR, the MORF, and other RNA-editing proteins. One selective factor for RNA editing might have been protection against the increased exposure to UV light when plants moved from water to land. This connection is attractive

considering the establishment of RNA editing only in the first land plants and its absence in the alga. However, the potential connection is presently not discernible because the most exposed nucleotide connections of TT dimers in the organellar DNA are not statistically more highly represented in the RNA-editing target sites than at unedited positions in the genomes. Furthermore, RNA editing is very frequent in Isoetes, but these plants have moved back to life underwater, where they are better protected from UV irradiation. Plastids and mitochondria possibly benefit from RNA editing, which could protect their genes and eventually their entire genomes from being transferred into the nucleus. This raison d’être could be on the level of the divergent genetic code being used, for example, in mammalian mitochondria. Any direct translocation of a gene encoded in the mitochondrial genome into the nuclear genome could not be functionally translated. The different nuclear decoding system in mammalia and the absence of RNA editing in plants will result in different, less well adapted proteins.

The Cost of RNA Editing Energetically, RNA editing seems a waste of resources and is outrageously expensive. Also, the sheer number of nuclear genes being devoted to this process in plastids and mitochondria are extremely costly in terms of genomic space. Furthermore, considerable energy must be spent on first synthesizing and incorporating C ribonucleotides and then converting these to U ribonucleotides in the RNA. RNA editing is certainly not essential for land plants, as the loss of editing in Marchantia proves. So why is RNA editing still rampant in plants, and why is it maintained in spite of being so expensive? Is RNA editing in plant organelles used for regulation of organellar processes? Even if such a use was secondarily acquired, the control of the two energy generating organelles by the nucleus may justify the expenses. Answers to these questions still require an evolutionary rationale.

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CONCLUSION Recent progress, mostly via genetic studies, revealed two types of key players in RNA editing in plant organelles: PPR proteins and MORF proteins. However, how these proteins cooperate is still unclear. Identification of the deaminase enzyme activity remains one of the main open questions in RNA editing in plants. The biological significance of RNA editing in plant organelles, beyond just being toler-

ated through, for example, a regulatory function of organellar genes, needs to be clarified. At present, there is little evidence to support such a function. The modular nature of sequence-specific RNA binding by the PPR proteins opens a new field of RNA biotechnology in which proteins analogous to the TALEN DNA-binding technology are built. The PPR proteins identified in RNA editing in plant organelles open applications up to interference with RNA virus infections.


SUMMARY POINTS 1. Individual RNA-editing sites are recognized by specific PPR proteins. 2. In flowering plants, approximately 200 of the 400 PPR proteins are involved in RNA editing, and the rest promote various other RNA-processing steps. 3. PPR proteins consist of approximately 35-mer amino acid–repeat units, each of which can contact a nucleotide in the RNA. 4. The PPR protein–RNA code has been solved to rely on two combinatorial amino acids. 5. In flowering plants, another group of proteins, the MORFs, are essential components of the RNA editosome and interact with PPR proteins.

FUTURE ISSUES 1. The actual editing enzyme needs to be identified. 2. The functions of the MORF proteins need to be investigated. 3. The connection between PPR specificity factors and MORF proteins should be analyzed.

DISCLOSURE STATEMENT The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS for excellent experimental We thank Dagmar Pruchner, Bianca Wolf, and Angelika Muller ¨ help. This work was supported by grants from the Deutsche Forschungsgemeinschaft to Mizuki Takenaka and Axel Brennicke. Mizuki Takenaka is a Heisenberg Fellow.

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Contents

Annual Review of Genetics Volume 47, 2013

Causes of Genome Instability Andrés Aguilera and Tatiana Garc´ıa-Muse p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1


Radiation Effects on Human Heredity Nori Nakamura, Akihiko Suyama, Asao Noda, and Yoshiaki Kodama p p p p p p p p p p p p p p p p p p p33 Dissecting Social Cell Biology and Tumors Using Drosophila Genetics José Carlos Pastor-Pareja and Tian Xu p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p51 Estimation and Partition of Heritability in Human Populations Using Whole-Genome Analysis Methods Anna A.E. Vinkhuyzen, Naomi R. Wray, Jian Yang, Michael E. Goddard, and Peter M. Visscher p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p75 Detecting Natural Selection in Genomic Data Joseph J. Vitti, Sharon R. Grossman, and Pardis C. Sabeti p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p97 Adaptive Translation as a Mechanism of Stress Response and Adaptation Tao Pan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 121 Organizing Principles of Mammalian Nonsense-Mediated mRNA Decay Maximilian Wei-Lin Popp and Lynne E. Maquat p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 139 Control of Nuclear Activities by Substrate-Selective and Protein-Group SUMOylation Stefan Jentsch and Ivan Psakhye p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 167 Genomic Imprinting: Insights From Plants Mary Gehring p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 187 Regulation of Bacterial Metabolism by Small RNAs Using Diverse Mechanisms Maksym Bobrovskyy and Carin K. Vanderpool p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 209 Bacteria and the Aging and Longevity of Caenorhabditis elegans Dennis H. Kim p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 233 The Genotypic View of Social Interactions in Microbial Communities Sara Mitri and Kevin Richard Foster p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 247 SIR Proteins and the Assembly of Silent Chromatin in Budding Yeast Stephanie Kueng, Mariano Oppikofer, and Susan M. Gasser p p p p p p p p p p p p p p p p p p p p p p p p p p p p 275 v

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New Gene Evolution: Little Did We Know Manyuan Long, Nicholas W. VanKuren, Sidi Chen, Maria D. Vibranovski p p p p p p p p p p p 307 RNA Editing in Plants and Its Evolution Mizuki Takenaka, Anja Zehrmann, Daniil Verbitskiy, Barbara Härtel, and Axel Brennicke p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 335 Expanding Horizons: Ciliary Proteins Reach Beyond Cilia Shiaulou Yuan and Zhaoxia Sun p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 353 The Digestive Tract of Drosophila melanogaster Bruno Lemaitre and Irene Miguel-Aliaga p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 377


RNase III: Genetics and Function; Structure and Mechanism Donald L. Court, Jianhua Gan, Yu-He Liang, Gary X. Shaw, Joseph E. Tropea, Nina Costantino, David S. Waugh, and Xinhua Ji p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 405 Modernizing the Nonhomologous End-Joining Repertoire: Alternative and Classical NHEJ Share the Stage Ludovic Deriano and David B. Roth p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 433 Enterococcal Sex Pheromones: Signaling, Social Behavior, and Evolution Gary M. Dunny p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 457 Control of Transcriptional Elongation Hojoong Kwak and John T. Lis p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 483 The Genomic and Cellular Foundations of Animal Origins Daniel J. Richter and Nicole King p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 509 Genetic Techniques for the Archaea Joel A. Farkas, Jonathan W. Picking, and Thomas J. Santangelo p p p p p p p p p p p p p p p p p p p p p p p 539 Initation of Meiotic Recombination: How and Where? Conservation and Specificities Among Eukaryotes Bernard de Massy p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 563 Biology and Genetics of Prions Causing Neurodegeneration Stanley B. Prusiner p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 601 Bacterial Mg2+ Homeostasis, Transport, and Virulence Eduardo A. Groisman, Kerry Hollands, Michelle A. Kriner, Eun-Jin Lee, Sun-Yang Park, and Mauricio H. Pontes p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 625 Errata An online log of corrections to Annual Review of Genetics articles may be found at http://genet.annualreviews.org/errata.shtml

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Contents

Progress in Genome Editing Technology and Its Application in Plants.

The evolution of RNA editing in kinetoplastid protozoa.

DNA and RNA editing of retrotransposons accelerate mammalian genome evolution.

Variable frequency of plastid RNA editing among ferns and repeated loss of uridine-to-cytidine editing from vascular plants.

RNA editing.

Parallel Evolution and Lineage-Specific Expansion of RNA Editing in Ctenophores.

Mitochondrial Genome Evolution and a Novel RNA Editing System in Deep-Branching Heteroloboseids.

RNA editing. Copy editing--what's the U's?

Antiviral Defenses in Plants through Genome Editing.

Genome editing with engineered nucleases in plants.

RNA editing in trypanosomatid mitochondria.

RNA editing: in Chloroplast and brain.

Reverse U-to-C editing exceeds C-to-U RNA editing in some ferns - a monilophyte-wide comparison of chloroplast and mitochondrial RNA editing suggests independent evolution of the two processes in both organelles.

Activity and specificity of TRV-mediated gene editing in plants.

Frequent chloroplast RNA editing in early-branching flowering plants: pilot studies on angiosperm-wide coexistence of editing sites and their nuclear specificity factors.

RNA editing by the host ADAR system affects the molecular evolution of the Zika virus.

RCARE: RNA Sequence Comparison and Annotation for RNA Editing.

RNA editing. Guides to experiments.

RNA editing: world's smallest introns?

Mediated plastid RNA editing in plant immunity.

Convergent Evolution of Fern-Specific Mitochondrial Group II Intron atp1i361g2 and Its Ancient Source Paralogue rps3i249g2 and Independent Losses of Intron and RNA Editing among Pteridaceae.

Conserved microRNA editing in mammalian evolution, development and disease.

Genome editing in plants via designed zinc finger nucleases.

Seamless editing of the chloroplast genome in plants.