Family of Pentatricopeptide Repeat Proteins in Non-Plant Organisms March 2018 Family of Pentatricopeptide Repeat Proteins in Non-Plant Organisms

Internal Medicine Review Family of pentatricopeptide repeat proteins in non-plant organisms March 2018 Family of pentatricopeptide repeat proteins in non-plant organisms

Authors Abstract Pentatricopeptide repeat (PPR) proteins belong to Czubak Pawel1 the large family of nucleic acid binding proteins. Their Raczynska Katarzyna name is defined by the presence of the so-called pentatricopeptide repeat (PPR), a degenerate 35-amino acid Dorota1 ⃰ motif tandemly repeated 2–26 times per protein. The PPR protein family includes some of the major mediators of organelle post-transcriptional control. These proteins Affiliation localize mainly to mitochondria and chloroplasts, where 1Department of Gene they are involved in different steps of RNA metabolism: transcription, splicing, editing, polyadenylation, RNA Expression, Institute of stability and translation. Some of them can also act as Molecular Biology and adaptors in protein-protein interactions. PPR protein genes were discovered in many eukaryotic genomes, but they are Biotechnology, Adam especially abundant in plants. In humans, some PPR Mickiewicz University in proteins are implicated in human diseases, such as cancer, Alzheimer’s disease and Parkinson’s disease. Poznan, Poznan, Poland.

Abbreviations AD - Alzheimer’s Disease; APP - amyloid beta precursor Correspondence protein; APPsw - APP carrying the so-called Swedish Raczynska Dorota, +48 mutation; DmLRPPRC - Drosophila melanogaster’s leucine-rich pentatricopeptide repeat-containing 61 829 5953; Fax: +48 61 homologue; HAT - half-A-TPR; KPAF1 - kinetoplast 829 5949; Email: polyadenylation/uridylation factor 1; KPAF2 - kinetoplast polyadenylation/uridylation factor 2; KPAP1- kinetoplast [email protected] poly(A) polymerase 1; KRIPP - kinetoplast ribosomal PPR protein; LSFC - Leigh syndrome French Canadian; LRPPRC - leucine-rich PPR cassette; LRRK2 (PARK8) - leucine rich repeat kinase 2; MRPS27 - mitochondrial ribosomal protein of the small subunit 27; MRPP3 - mitochondrial RNase P protein 3; PD-Parkinson’s disease; POLRMT - RNA polymerase, mitochondrial; PPR - pentatricopeptide repeat; PTCD - pentatricopeptide repeat domain; PSEN – presenilin; PTEN - phosphatase and tensin; PUF - Pumilio and FBF homology; RBP – RNA binding protein; RET1 TUTase - RNA editing TUTase 1; SEL-1 - suppressor of Lin-12; SLIRP - SRA - stem-loop- interacting RNA binding protein; TALE - transcription activator-like effector; TMG - tRNA guanine-N7 methyltransferase; TPR – tetratricopeptide repeat.

Pentatricopeptide repeat proteins Pentatricopeptide repeat proteins structure Pentatricopeptide repeat proteins were first described in 2000 as “PPR The PPR is a degenerate, 35-amino- cassette proteins” by Small and Peeters (1). acid motif repeated in tandem. The number The main feature of PPR proteins is the of motifs ranges from 2 to over 26 within a presence of a 35-amino acid protein (1, 2). The PPR motif forms two (pentatricopeptide) structural motif that is anti-parallel α-helices that interact to tandemly repeated 2–26 times per protein produce a helix-turn-helix motif. The series (1). Initially, PPR proteins were thought to of helix-turn-helix motifs throughout the bind proteins. Further investigations protein stack on each other to form an revealed that the PPR domain is involved elongated structure called a superhelix, in RNA–protein interactions (1, 2). with a central groove that binds RNA. Therefore, PPR proteins belong to a class Residues at position 4 and 34 of each PPR of RNA binding proteins (RBPs) referred motif are responsible for modular to as heterogeneous ribonucleoproteins that recognition of sequence motifs within the associate with certain transcripts and transcript (Fig.1) (2, 20-23). influence all steps of post-transcriptional The sequence of the PPR motif is regulation of RNAs, including pre-mRNA similar to the closely related splicing, mRNA polyadenylation, tetratricopeptide repeat (TPR) motif that is localization, stability and translation. Some prevalent in prokaryotes. Therefore, some RBPs can mediate RNA transport from the have hypothesized that the PPR motif nucleus to mitochondria and from emerged from the TPR motif during the mitochondria to the nucleus (3-6). early stages of eukaryotic evolution (10). PPR proteins are found in all PPR motifs, together with the TPR motif, eukaryotes, though they are most prevalent the suppressor of Lin-12 (SEL-1)–like in plants (7-11). For example, in motif and the half-A-TPR (HAT) repeats, Arabidopsis thaliana, there are 441 PPR belong to a large family of solenoid repeat proteins. They belong to one of the largest structures formed of α-α repeats (1, 24, nucleus-encoded helical repeat protein 25). Similar to Pumilio and FBF homology families in plants (1, 12-15). Some PPR- (PUFs) and transcription activator-like encoding genes have also been found in effector (TALE) proteins, PPR proteins prokaryotes, including pathogenic and interact with nucleic acids in a sequence- symbiotic members of the genera dependent manner. Therefore, they are Rhodobacter, Ralstonia, Simkania, very specific according to the locations of Erwinia and Legionella. They are thought individual editing sites within organelle to have been acquired via eukaryote-to- transcriptomes (26-28). In contrast, the prokaryote horizontal gene transfer events interaction of TPR proteins with RNA is (2, 10, 16-19). sequence independent (29, 30).

Figure 1. Schematic structure of the PPR protein and the mechanism of RNA recognition. Each helix-turn-helix motif is formed by two α-helices included in the PPR domain. Helix- turn-helix motifs form a superhelix, containing an RNA binding groove. Amino acids at positions 4 and 34 of each PPR motifs are responsible for modular transcripts recognition (adopted from (31)). 3 Copyright 2018 Internal Medicine Review. All Rights Reserved. Volume 4, Issue 3. Internal Medicine Review Family of pentatricopeptide repeat proteins in non-plant organisms March 2018

Yeast PPR motifs are quite similar (DYW) tripeptide located at the C- to plant PPR motifs, although in yeasts, the terminus. DYW domains contain the same PPR motifs are significantly more conserved catalytic residues as cytidine divergent. Thus, according to the deaminase enzymes, which mediate C-to-U evolutionary distance between yeasts and conversion. Thus, the DYW domain has plants and the relatively sparse knowledge been proposed to be an editing domain. about yeast PPRs, we cannot assume that Therefore, the presence of PLS class PPR substrate recognition uses the same proteins correlates with the occurrence of residues in the PPR motifs. Similarly, organelle RNA editing, and they are absent Trypanosoma motifs and human motifs in organisms where organelle RNA editing also show evolutionary divergence, and does not occur. The PLS class was their sequences are different from the originally thought to be specific to plants, general motif consensus observed in but the DYW-containing PPR proteins plants. However, although the PPR motifs were subsequently identified in the in different organisms differ, the key heterolobosean protist Naegleria gruberi residues are often partially conserved (7, and later in several non-plant organisms. 32). Therefore, DYW-type PPR proteins are There are two PPR classes that thought to have been acquired from plants differ by their domain architecture: P-class via horizontal gene transfer events. and PLS-class. P-class PPR proteins It is worth mentioning that PPR possess the canonical 35-amino-acid proteins differ according to the content of motifs without additional domains (P domains. Some of them are built almost means canonical PPR). Members of this entirely of tandem PPRs, whereas others class play roles in most aspects of contain different domains, such as organelle gene expression and commonly endonuclease or protein interaction regulate RNA processing, splicing, domains (2, 34, 35). For example, the PPR stability and translation. PLS-class PPR protein in Trypanosoma brucei, PtcE, proteins have three different types of PPR contains a C-terminal methyltransferase motifs, which vary in length: P (PPR, 35 domain. As the domain is thought to be amino acids), L (long, 35-36 amino acids) active, PtcE, like PPR proteins in D. and S (short, ~31 amino acids). Members discoideum mitochondria, is a potential of this class mainly function in RNA candidate that can modify the stability of editing (2, 31, 33). Subtypes of the PLS mitochondrial transcripts by introducing class are further categorized based on posttranscriptional modification (9). additional C-terminal domains: motif E (91 In 2008, the crystal structure of amino acids), motif E+ (33 amino acids) human mitochondrial RNA polymerase II, and motif DYW (106 aminoacids). The also called POLRMT (RNA polymerase first PLS subclass contains motif E, which mitochondrial), was revealed (36). It is not catalytic but is predicted to be a contains a T7-like catalytic C-terminal protein-protein interaction motif that domain, an N-terminal domain (with a T7 recruits the editing enzyme. The second promoter binding domain) and a flexible PLS subclass contains E, E+ and DYW N-terminal extension. The N-terminal domains. The DYW domain was named domain consists of nine α-helices, four of for its aspartate-tyrosine-tryptophan which comprise two PPR motifs found in

4 Copyright 2018 Internal Medicine Review. All Rights Reserved. Volume 4, Issue 3. Internal Medicine Review Family of pentatricopeptide repeat proteins in non-plant organisms March 2018 plant mitochondrial proteins. Each PPR binding proteins because of the low motif forms the hydrophobic core of a number of promoters in organelle genomes helix–turn–helix fold and the interface and the long half-life of organelle RNAs. between parallel and antiparallel α-helices In this way, members of the PPR protein (36). family are some of the major mediators of To better understand the expression of organelle genomes and mechanism of PPR-RNA binding, organelle biogenesis (1, 2, 12, 31, 38). Rackham’s group designed synthetic PPR PPR proteins can also be non- domains based on the conservation of catalytic, in which case they function as residues within PPRs throughout evolution molecular adaptors in the recruitment of (37). Interestingly, they were able to catalytic enzymes or effector proteins to generate different PPR variants with target transcripts (39, 40). However, they altered affinities or degenerate nucleotide can also catalyse RNA processing and recognition properties by introducing some editing themselves (2, 26). Several PPR changes in PPR sequence. For example, proteins act as stability and/or translation the presence of phenylalanine at position 1 factors, and their absence leads to both the and asparagine at positions 4 and 34 destabilization of a given mitochondrial favoured binding to adenine and guanine, mRNA and a defect in the accumulation of while valine at position 1 favoured binding the corresponding protein. However, it is to adenine and cytosine. Therefore, the still not clear whether these factors have a synthetic domains could recognize RNA dual role in stability and translation, as was targets of interest in a predictable shown, for example, for PPR10 in sequence-specific manner according to the Arabidopsis chloroplasts. An alternative appropriate amino acid at positions 1, 4 hypothesis assume that i) a primary RNA and 34 (37). Interestingly, it was also stability defect causes a secondary suggested that the overall shape of the PPR translation deficiency or ii) a primary scaffold partially depends on the amino defect in translation destabilizes the acids that mediate RNA association. mitochondrial mRNA (32). Moreover, mutual interactions of PPR The most common function of plant repeats resulted in some plasticity of the PPR proteins is RNA editing (8, 13, 38). In PPR scaffold that enabled it to modulate contrast, in Trypanosoma brucei, the RNA binding properties of PPRs (37). approximately half of the 39 PPR proteins identified have been detected in affinity- Pentatricopeptide repeat protein purified ribosomal particles from the functions kinetoplast, a dense nucleoprotein structure containing the mitochondrial genome. PPR proteins are mainly localized They were termed kinetoplast ribosomal to mitochondria, where they play various PPR proteins (KRIPPs), and they are roles at different steps of RNA metabolism: considered translational activators for a transcription, transcript processing, subset of mitochondrial mRNAs (41, 42). splicing, editing, polyadenylation, RNA Some PPR proteins, such as kinetoplast stability and translation. Regulation of polyadenylation/uridylation factors organelle gene expression at the post- (KPAF) 1 and 2, are involved in transcriptional level depends on RNA stabilization and polyadenylation of

5 Copyright 2018 Internal Medicine Review. All Rights Reserved. Volume 4, Issue 3. Internal Medicine Review Family of pentatricopeptide repeat proteins in non-plant organisms March 2018 kinetoplast transcripts. They have been the metabolism of mitochondrial identified in the polyadenylation complex transcripts (46). In addition to and facilitate the A/U-tailing of mRNA mitochondria, LRPPRC is present in the 3’ends by kinetoplast poly(A) polymerase nucleus, where it is involved in the 1 (KPAP1) and RNA editing TUTase 1 regulation of mitochondrial biogenesis and (RET1 TUTase). Others, such as KRIPP1 energy homeostasis by controlling nuclear and KRIPP8, have been identified both in gene expression. In this way, LRPPRC the polyadenylation complex and in the might play a role in coordinating small ribosomal subunit. Therefore, PPR mitochondrial transcription with nuclear proteins can serve as protein adaptors in gene expression, which is critical for regulatory networks that channel mRNAs proper organelle function (50). for 3′ A/U-tailing and translation (41-43). Recently, a whole new family of Although not as numerous as in PPR proteins - PPR-TGM (PPR-tRNA plants and trypanosomes, PPR proteins guanine-N7 methyltransferase) proteins, from other organisms also participate in were discovered. What is interesting, PPR- translational control of mitochondrial TGM proteins are missing in plants and mRNAs. In S. cerevisiae and closely animals. Instead, they are found in single- related species, PPR proteins facilitate celled eukaryotic microbes organisms, initiation of translation by recognizing and including cellular slime moulds, binding to the 5′ UTRs of specific mRNAs. entamoebae, algae and diatoms. In addition Thus, they act as mitochondrial mRNA- to the PPR tract, these proteins contain a specific translational activators and are a C-terminal tRNA guanine-N7 part of the feedback control loop that methyltransferase domain originated from adjusts the translation rate to the assembly a chlamydial TGM-encoding gene, of nascent polypeptides into respective acquired via horizontal gene transfer from respiratory complexes (32, 44). In humans, bacteria. The domain architecture of PPR- leucine-rich pentatricopeptide repeat- TGM proteins suggests they function in containing (LRPPRC) protein stimulates tRNA metabolism both in mitochondria, poly(A) polymerase for mRNA chloroplasts and in the cytoplasm (51). polyadenylation to protect protein- In mammals, seven PPR proteins encoding transcripts from the have been identified to date: POLRMT, mitochondrial degradosome activity. pentatricopeptide repeat domain 1 Similarly, Drosophila melanogaster’s (PTCD1), PTCD2, PTCD3, LRPPRC, homologue DmLRPPRC1 is necessary for mitochondrial ribosomal protein S27 mitochondrial mRNA polyadenylation. (MRPS27) and mitochondrial RNase P Loss of the LRPPRC or DmLRPPRC protein 3 (MRPP3). They are mainly protein leads to decreased stability of localized in mitochondria and regulate mitochondrial transcripts and reduction of transcription, transcript processing, RNA their abundance (45-49). stability and translation, not RNA editing LRPPRC associates with SRA (Table 1) (31, 52-58). However, the stem-loop-interacting RNA binding protein physiological targets of PPR proteins are (SLIRP), a mitochondrial RBP. Both often unknown, which limits the proteins are part of a high-molecular-mass understanding of their mechanistic roles in ribonucleoprotein complex that regulates organelle gene expression and energy

metabolism.

Table 1. PPR proteins and their function in human cells. Protein Short name Function Gene location Mitochondrial RNA polymerase II POLRMT mitochondrial gene expression, initiation 19p13.3 of the mitochondrial genome replication Pentatricopeptide repeat domain 1 PTCD1 RNA binding, regulation of translation 7q22.1 Pentatricopeptide repeat domain 2 PTCD2 mitochondrial RNA maturation, 5q13.2 mitochondrial respiratory chain function Pentatricopeptide repeat domain 3 PTCD3 mitochondrial translation, organelle 2p11.2 biogenesis and maintenance Leucine-rich pentatricopeptide- LRPPRC cytoskeletal organization, vesicular 2p21 repeat containing protein transport, transcriptional regulation of both nuclear and mitochondrial genes Mitochondrial ribosomal protein MRPS27 mitochondrial protein synthesis, 5q13.2 S27 stimulation of mitochondrial mRNA translation of subunit components of the mitochondrial electron transport chain Mitochondrial RNase P protein 3 KIAA0391 mitochondrial tRNA maturation 14q13.2 (MRPP3)

Pentatricopeptide repeat proteins in apoptosis, invasion, and in vitro colony medicine formation abilities of lung adenocarcinoma and Hodgkin lymphoma cells. This LRPPRC is one of the best-studied suggests that the knock-down of LRPPRC PPR proteins, as it is implicated in human could be one strategy to prevent diseases, such as cancer. The connection carcinogenesis (60). between cancer and mitochondria is based LRPPR proteins can also be used as on the accelerated energy consumption of a specific biomarkers, for instance, in tumour cells. As LRPPRC plays an prostate cancer. Prostate cancer is the most important role in mitochondrial function, it common non-cutaneous malignancy and is also necessary for tumour development. the second leading cause of cancer death Indeed, LRPPRC is abundantly expressed among men in the United States (61). By in various types of tumours, such as lung immunochemistry analysis Jiang et al. (62) adenocarcinoma cell lines, oesophageal showed that prostate tissues at late stage of squamous cell carcinoma, lung prostate adenocarcinomas express higher adenocarcinoma, stomach level of LRPPRC. Moreover, LRPPRC adenocarcinoma, colon adenocarcinoma, levels were significantly lower in patients mammary adenocarcinoma, endometrial surviving longer than five or ten years than adenocarcinoma and lymphoma (59, 60). in patients surviving shorter than five or Moreover, the overexpression of LRPPRC ten years. From this reason the level of confers resistance to apoptosis of tumour LRPPRC can be a biomarker for late-stage cells (60). In agreement with this, knock- prostate adenocarcinomas patients with down of LRPPRC reduced the anti- poor prognosis (62). They also confirmed

7 Copyright 2018 Internal Medicine Review. All Rights Reserved. Volume 4, Issue 3. Internal Medicine Review Family of pentatricopeptide repeat proteins in non-plant organisms March 2018 the association of high LRPPRC levels The etiology of AD is mostly sporadic with hormone therapy insensitivity in (95% of the cases) and have a late onset at prostate adenocarcinomas tissue samples about the age of 65. The risk of AD collected from prostate-specific occurrence can be altered by various phosphatase and tensin homolog (PTEN) environmental exposures, such as nutrition, deficient mice or hormone-dependent and smoking, head trauma, infections or independent prostate cancer cell lines (62). systemic inflammation, as well as Mitochondrial pathophysiology due psychosocial factors, such as education or to mutation in the LRPPRC gene underlies physical activity (67). AD pathogenesis a human neurodegenerative disorder, the may also be due to epigenetic mechanisms. French-Canadian variant of Leigh Studies on human postmortem brain syndrome (Leigh syndrome French samples, peripheral leukocytes and Canadian; LSFC). Individuals with LSFC transgenic animal models have revealed often appear normal at birth but begin to that AD is strongly linked to aging and lose basic skills such as head control, epigenetic deregulations, including sucking, walking, and talking in infancy or abnormal DNA methylation and histone early childhood. They may also present modifications (67, 68). with intellectual disabilities, dysmorphic In contrast, in case of the familial features, irritability, vomiting, form of AD (5% of cases) some early onset and seizures. At the molecular level, LSFC cases were reported. Familiar form of AD is caused by a point mutation in the gene is connected with the mutations in the encoding LRPPRC that affects the stability genes encoding amyloid precursor protein of most mitochondrial mRNAs. However, (APP), presenilin-1 (PSEN1) and LSFC’s pathophysiological effect has presenilin-2 (PSEN2) (69). LRPPRC mainly been attributed to a reduced level of preferentially interacts with amyloid beta cytochrome c oxidase mRNA. This in turn precursor protein carrying the so-called results in defective cytochrome oxidase Swedish mutation (APPsw). Such assembly and deficiencies of mitochondrial interaction is responsible for some cases of complex I, complex IV and ATP synthase. early-onset Alzheimer’s disease (70). As a final consequence, mitochondrial Examination of the brains from respiration and ATP production are Alzheimer patients compared with controls impaired (63-66). At the molecular level, shows an elevated levels of another human the LRPPRC protein shows some PPR protein, PTCD2, in the cerebral cortex homology to the yeast protein PET309, of AD patients (71). Therefore, PTCD2 can which is also required for the efficient also be used as a biomarker for Alzheimer expression of theCOX gene (63, 66). disease (AD). LRPPRC protein is also thought to Parkinson’s disease (PD) is another be involved in the occurrence of sporadic neurodegenerative disorder linked to Alzheimer’s disease (AD) cases. The mutation in PPR protein gene. Parkinson’s Alzheimer’s Disease is characterized by disease is characterized by tremor, inflammatory changes, accumulation of bradykinesia, rigidity and postural misfolded proteins and oxidative damage, instability. First symptom of about 70% which results in region-specific loss of cases of disease is motoric instabilities synaptic contacts and neuronal cell death. with resting tremor at a typical frequency

8 Copyright 2018 Internal Medicine Review. All Rights Reserved. Volume 4, Issue 3. Internal Medicine Review Family of pentatricopeptide repeat proteins in non-plant organisms March 2018 of 3–5 Hz (72). PD neurodegeneration is Nowadays, when we are able to thought to be caused by genetic and manipulate or design PPR proteins that environmental risk factors and interactions recognize any RNA sequence we want, the between them, that leads to the neuronal possible application in medicine are death. As a risk factor of PD some opened. By introducing mutations into the environmental toxins (such as rotenone and coding sequence of known PPR protein we paraquat) and other factors causing can change the crucial amino acids and mitochondrial dysfunction have been direct the binding of the PPR protein to an reported. 90% of PD cases are sporadic, RNA sequence of interest (22). Moreover, the remaining 10% of cases show familiar synthetic PPR protein (37) can be used to inheritance. In the latter cases, mutations in replace a dysfunctional PPR protein, to the leucine rich repeat kinase 2 (LRRK2, regulate endogenous gene expression or PARK8) are the most frequent (73). even to prevent viral infections by Parkinson’s disease (PD) is also blocking the synthesis of viral RNA. One associated with mutations in the of the most interesting are PPR-TGM pentatricopeptide repeat protein gene - proteins, that are important to the LRPPRC gene. At the molecular level, four clinically-relevant pathogens but are absent intronic substitutions influence the splicing in humans. Therefore, PPR-TGM proteins of the LRPPRC pre-mRNA, leading to represent new putative targets for the skipping of some exons (e.g., exon 9 or development of drugs that can specifically exon 33). This leads to the creation of a inhibit their activity in pathogenic premature stop codon that targets the eukaryotes. Drugs, developed to block mature mRNA for further degradation by PPR-TGM function in parasites, can the nonsense mediated decay (NMD) effectively treat parasitic infections pathway. LRPPRC protein depletion without any effects on the human body causes mitochondrial dysfunction. (51). Interestingly, due to the tissue-specific availability of some splicing factors, a Conclusions given mutation can have different effects in different tissues. LRPPRC mutations PPR proteins are important for linked to the origin and progression of expression of organelle genomes and disease are observed mainly in organs organelle biogenesis. Some of them are where the LRPPRC steady-state level is implicated in human diseases, such as quite low. Moreover, the clinical impact of cancer, Alzheimer’s disease and the LRPPRC mutation depends on whether Parkinson’s disease. Further analysis of the mutation is homozygous or their functions and targets will help to heterozygous. Finally, some intronic describe the molecular pathways LRPPRC variants could lead to complete underlying these human disorders. The or partial LRPPRC protein depletion or to precise knowledge of PPR proteins’ actions its functional changes, which can influence and the molecular consequences of their the risk of Parkinson’s disease and other disruption can also be useful in designing neurodegenerative disorders (e.g., LSFC) therapeutic strategies for patients. A (66, 74, 75). promising avenue for future research is synthetic domains based on PPR motifs

9 Copyright 2018 Internal Medicine Review. All Rights Reserved. Volume 4, Issue 3. Internal Medicine Review Family of pentatricopeptide repeat proteins in non-plant organisms March 2018 that can recognize RNA targets of interest 2016/21/B/NZ1/00232 (to KDR); KNOW in a predictable, sequence-specific manner. RNA Research Centre in Poznan under Therefore, PPR proteins could be used to grant 01/KNOW2/2014 (to PC, KDR). regulate particular gene transcripts’ expression.

Acknowledgments

Funding This work was supported by: Polish Science Centre under grant UMO-

References 11. O'Toole N, Hattori M, Andres C, 1. Small ID, Peeters N. The PPR Iida K, Lurin C, Schmitz-Linneweber C, et motif - a TPR-related motif prevalent in al. On the expansion of the plant organellar proteins. Trends Biochem pentatricopeptide repeat gene family in Sci. 2000;25(2):46-7. plants. Mol Biol Evol. 2008;25(6):1120-8. 2. Schmitz-Linneweber C, Small I. 12. Raczynska KD, Augustyniak H. Pentatricopeptide repeat proteins: a socket [Family of pentatricopeptide repeat set for organelle gene expression. Trends proteins]. Postepy Biochem. Plant Sci. 2008;13(12):663-70. 2005;51(4):440-6. 3. Dong Y, Yoshitomi T, Hu JF, Cui J. 13. Hassani D, Khalid M, Bilal M, Long noncoding RNAs coordinate Zhang YD, Huang D. Pentatricopeptide functions between mitochondria and the repeat-directed RNA editing and their nucleus. Epigenetics Chromatin. biomedical applications. International 2017;10(1):41. Journal of Pharmacology. 2017;13(7):762- 4. Moore MJ. From birth to death: the 72. complex lives of eukaryotic mRNAs. 14. Filipovska A, Rackham O. Science. 2005;309(5740):1514-8. Pentatricopeptide repeats: modular blocks 5. Dreyfuss G, Kim VN, Kataoka N. for building RNA-binding proteins. RNA Messenger-RNA-binding proteins and the Biol. 2013;10(9):1426-32. messages they carry. Nat Rev Mol Cell 15. Lurin C, Andres C, Aubourg S, Biol. 2002;3(3):195-205. Bellaoui M, Bitton F, Bruyere C, et al. 6. Keene JD. RNA regulons: Genome-wide analysis of Arabidopsis coordination of post-transcriptional events. pentatricopeptide repeat proteins reveals Nat Rev Genet. 2007;8(7):533-43. their essential role in organelle biogenesis. 7. Lipinski KA, Puchta O, Plant Cell. 2004;16(8):2089-103. Surendranath V, Kudla M, Golik P. 16. Cazalet C, Gomez-Valero L, Revisiting the yeast PPR proteins-- Rusniok C, Lomma M, Dervins-Ravault D, application of an Iterative Hidden Markov Newton HJ, et al. Analysis of the Model algorithm reveals new members of Legionella longbeachae genome and the rapidly evolving family. Mol Biol Evol. transcriptome uncovers unique strategies to 2011;28(10):2935-48. cause Legionnaires' disease. PLoS Genet. 8. Shikanai T. RNA editing in plant 2010;6(2):e1000851. organelles: machinery, physiological 17. Choudhary M, Zanhua X, Fu YX, function and evolution. Cell Mol Life Sci. Kaplan S. Genome analyses of three strains 2006;63(6):698-708. of Rhodobacter sphaeroides: evidence of 9. Manna S, Brewster J, Barth C. rapid evolution of chromosome II. J Identification of Pentatricopeptide Repeat Bacteriol. 2007;189(5):1914-21. Proteins in the Model Organism 18. Hallam SJ, Putnam N, Preston CM, Dictyostelium discoideum. Int J Genomics. Detter JC, Rokhsar D, Richardson PM, et 2013;2013:586498. al. Reverse methanogenesis: testing the 10. Barkan A, Small I. hypothesis with environmental genomics. Pentatricopeptide repeat proteins in plants. Science. 2004;305(5689):1457-62. Annu Rev Plant Biol. 2014;65:415-42. 19. Schallenberg-Rudinger M, Lenz H,

Polsakiewicz M, Gott JM, Knoop V. A to its native group II intron ligand. RNA. survey of PPR proteins identifies DYW 2008;14(9):1930-41. domains like those of land plant RNA 28. Okuda K, Myouga F, Motohashi R, editing factors in diverse eukaryotes. RNA Shinozaki K, Shikanai T. Conserved Biol. 2013;10(9):1549-56. domain structure of pentatricopeptide 20. Ke J, Chen RZ, Ban T, Zhou XE, repeat proteins involved in chloroplast Gu X, Tan MH, et al. Structural basis for RNA editing. Proc Natl Acad Sci U S A. RNA recognition by a dimeric PPR-protein 2007;104(19):8178-83. complex. Nat Struct Mol Biol. 29. Abbas YM, Pichlmair A, Gorna 2013;20(12):1377-82. MW, Superti-Furga G, Nagar B. Structural 21. Yin P, Li Q, Yan C, Liu Y, Liu J, Yu basis for viral 5'-PPP-RNA recognition by F, et al. Structural basis for the modular human IFIT proteins. Nature. recognition of single-stranded RNA by 2013;494(7435):60-4. PPR proteins. Nature. 30. Pichlmair A, Lassnig C, Eberle CA, 2013;504(7478):168-71. Gorna MW, Baumann CL, Burkard TR, et 22. Barkan A, Rojas M, Fujii S, Yap A, al. IFIT1 is an antiviral protein that Chong YS, Bond CS, et al. A combinatorial recognizes 5'-triphosphate RNA. Nat amino acid code for RNA recognition by Immunol. 2011;12(7):624-30. pentatricopeptide repeat proteins. PLoS 31. Manna S. An overview of Genet. 2012;8(8):e1002910. pentatricopeptide repeat proteins and their 23. Yagi Y, Hayashi S, Kobayashi K, applications. Biochimie. 2015;113:93-9. Hirayama T, Nakamura T. Elucidation of 32. Herbert CJ, Golik P, Bonnefoy N. the RNA recognition code for Yeast PPR proteins, watchdogs of pentatricopeptide repeat proteins involved mitochondrial gene expression. RNA Biol. in organelle RNA editing in plants. PLoS 2013;10(9):1477-94. One. 2013;8(3):e57286. 33. Hall TM. De-coding and re-coding 24. Main ER, Stott K, Jackson SE, RNA recognition by PUF and PPR repeat Regan L. Local and long-range stability in proteins. Curr Opin Struct Biol. tandemly arrayed tetratricopeptide repeats. 2016;36:116-21. Proc Natl Acad Sci U S A. 34. Gobert A, Gutmann B, Taschner A, 2005;102(16):5721-6. Gossringer M, Holzmann J, Hartmann RK, 25. Kobe B, Kajava AV. When protein et al. A single Arabidopsis organellar folding is simplified to protein coiling: the protein has RNase P activity. Nat Struct continuum of solenoid protein structures. Mol Biol. 2010;17(6):740-4. Trends Biochem Sci. 2000;25(10):509-15. 35. Takenaka M, Zehrmann A, 26. Delannoy E, Stanley WA, Bond CS, Verbitskiy D, Kugelmann M, Hartel B, Small ID. Pentatricopeptide repeat (PPR) Brennicke A. Multiple organellar RNA proteins as sequence-specificity factors in editing factor (MORF) family proteins are post-transcriptional processes in required for RNA editing in mitochondria organelles. Biochem Soc Trans. 2007;35(Pt and plastids of plants. Proc Natl Acad Sci 6):1643-7. U S A. 2012;109(13):5104-9. 27. Williams-Carrier R, Kroeger T, 36. Ringel R, Sologub M, Morozov YI, Barkan A. Sequence-specific binding of a Litonin D, Cramer P, Temiakov D. chloroplast pentatricopeptide repeat protein Structure of human mitochondrial RNA

12 Copyright 2018 Internal Medicine Review. All Rights Reserved. Volume 4, Issue 3. Internal Medicine Review Family of pentatricopeptide repeat proteins in non-plant organisms March 2018 polymerase. Nature. 2011;478(7368):269- 45. Richter-Dennerlein R, Dennerlein 73. S, Rehling P. Integrating mitochondrial 37. Coquille S, Filipovska A, Chia T, translation into the cellular context. Nat Rajappa L, Lingford JP, Razif MF, et al. An Rev Mol Cell Biol. 2015;16(10):586-92. artificial PPR scaffold for programmable 46. Sasarman F, Brunel-Guitton C, RNA recognition. Nat Commun. Antonicka H, Wai T, Shoubridge EA, 2014;5:5729. Consortium L. LRPPRC and SLIRP 38. Fujii S, Small I. The evolution of interact in a ribonucleoprotein complex RNA editing and pentatricopeptide repeat that regulates posttranscriptional gene genes. New Phytol. 2011;191(1):37-47. expression in mitochondria. Mol Biol Cell. 39. Matsushima Y, Hirofuji Y, Aihara 2010;21(8):1315-23. M, Yue S, Uchiumi T, Kaguni LS, et al. 47. Bratic A, Wredenberg A, Gronke S, Drosophila protease ClpXP specifically Stewart JB, Mourier A, Ruzzenente B, et degrades DmLRPPRC1 controlling al. The bicoid stability factor controls mitochondrial mRNA and translation. Sci polyadenylation and expression of specific Rep. 2017;7(1):8315. mitochondrial mRNAs in Drosophila 40. Barros MH, Tzagoloff A. Aep3p- melanogaster. PLoS Genet. dependent translation of yeast 2011;7(10):e1002324. mitochondrial ATP8. Mol Biol Cell. 48. Ruzzenente B, Metodiev MD, 2017;28(11):1426-34. Wredenberg A, Bratic A, Park CB, Camara 41. Aphasizheva I, Maslov D, Wang X, Y, et al. LRPPRC is necessary for Huang L, Aphasizhev R. Pentatricopeptide polyadenylation and coordination of repeat proteins stimulate mRNA translation of mitochondrial mRNAs. adenylation/uridylation to activate EMBO J. 2012;31(2):443-56. mitochondrial translation in trypanosomes. 49. Chujo T, Ohira T, Sakaguchi Y, Mol Cell. 2011;42(1):106-17. Goshima N, Nomura N, Nagao A, et al. 42. Aphasizheva I, Maslov DA, Qian Y, LRPPRC/SLIRP suppresses PNPase- Huang L, Wang Q, Costello CE, et al. mediated mRNA decay and promotes Ribosome-associated pentatricopeptide polyadenylation in human mitochondria. repeat proteins function as translational Nucleic Acids Res. 2012;40(16):8033-47. activators in mitochondria of 50. Cooper MP, Qu L, Rohas LM, Lin trypanosomes. Mol Microbiol. J, Yang W, Erdjument-Bromage H, et al. 2016;99(6):1043-58. Defects in energy homeostasis in Leigh 43. Ridlon L, Skodova I, Pan S, Lukes syndrome French Canadian variant through J, Maslov DA. The importance of the 45 S PGC-1alpha/LRP130 complex. Genes Dev. ribosomal small subunit-related complex 2006;20(21):2996-3009. for mitochondrial translation in 51. Manna S, Barth C. Identification of Trypanosoma brucei. J Biol Chem. a novel pentatricopeptide repeat subfamily 2013;288(46):32963-78. with a C-terminal domain of bacterial 44. Herrmann JM, Woellhaf MW, origin acquired via ancient horizontal gene Bonnefoy N. Control of protein synthesis transfer. BMC Res Notes. 2013;6:525. in yeast mitochondria: the concept of 52. Rackham O, Filipovska A. The role translational activators. Biochim Biophys of mammalian PPR domain proteins in the Acta. 2013;1833(2):286-94. regulation of mitochondrial gene

13 Copyright 2018 Internal Medicine Review. All Rights Reserved. Volume 4, Issue 3. Internal Medicine Review Family of pentatricopeptide repeat proteins in non-plant organisms March 2018 expression. Biochim Biophys Acta. 61. Siegel R, Naishadham D, Jemal A. 2012;1819(9-10):1008-16. Cancer statistics, 2013. CA Cancer J Clin. 53. Siira SJ, Spahr H, Shearwood AJ, 2013;63(1):11-30. Ruzzenente B, Larsson NG, Rackham O, et 62. Jiang X, Li X, Huang H, Jiang F, al. LRPPRC-mediated folding of the Lin Z, He H, et al. Elevated levels of mitochondrial transcriptome. Nat mitochondrion-associated autophagy Commun. 2017;8(1):1532. inhibitor LRPPRC are associated with poor 54. Perks KL, Ferreira N, Richman TR, prognosis in patients with prostate cancer. Ermer JA, Kuznetsova I, Shearwood AJ, et Cancer. 2014;120(8):1228-36. al. Adult-onset obesity is triggered by 63. Mootha VK, Lepage P, Miller K, impaired mitochondrial gene expression. Bunkenborg J, Reich M, Hjerrild M, et al. Sci Adv. 2017;3(8):e1700677. Identification of a gene causing human 55. Lightowlers RN, Chrzanowska- cytochrome c oxidase deficiency by Lightowlers ZM. Human pentatricopeptide integrative genomics. Proc Natl Acad Sci proteins: only a few and what do they do? U S A. 2003;100(2):605-10. RNA Biol. 2013;10(9):1433-8. 64. Mourier A, Ruzzenente B, Brandt 56. Rossmanith W. Of P and Z: T, Kuhlbrandt W, Larsson NG. Loss of mitochondrial tRNA processing enzymes. LRPPRC causes ATP synthase deficiency. Biochim Biophys Acta. 2012;1819(9- Hum Mol Genet. 2014;23(10):2580-92. 10):1017-26. 65. Sasarman F, Nishimura T, 57. Xu F, Ackerley C, Maj MC, Addis Antonicka H, Weraarpachai W, Shoubridge JB, Levandovskiy V, Lee J, et al. EA, Consortium L. Tissue-specific Disruption of a mitochondrial RNA- responses to the LRPPRC founder binding protein gene results in decreased mutation in French Canadian Leigh cytochrome b expression and a marked Syndrome. Hum Mol Genet. reduction in ubiquinol-cytochrome c 2015;24(2):480-91. reductase activity in mouse heart 66. Xu F, Morin C, Mitchell G, mitochondria. Biochem J. 2008;416(1):15- Ackerley C, Robinson BH. The role of the 26. LRPPRC (leucine-rich pentatricopeptide 58. Rorbach J, Minczuk M. The post- repeat cassette) gene in cytochrome transcriptional life of mammalian oxidase assembly: mutation causes mitochondrial RNA. Biochem J. lowered levels of COX (cytochrome c 2012;444(3):357-73. oxidase) I and COX III mRNA. Biochem J. 59. Seo DC, Sung JM, Cho HJ, Yi H, 2004;382(Pt 1):331-6. Seo KH, Choi IS, et al. Gene expression 67. Chouliaras L, Sierksma AS, Kenis profiling of cancer stem cell in human lung G, Prickaerts J, Lemmens MA, Brasnjevic adenocarcinoma A549 cells. Mol Cancer. I, et al. Erratum: gene-environment 2007;6:75. interaction research and transgenic mouse 60. Tian T, Ikeda J, Wang Y, Mamat S, models of Alzheimer's disease. Int J Luo W, Aozasa K, et al. Role of leucine- Alzheimers Dis. 2011;2010:356862. rich pentatricopeptide repeat motif- 68. Day JJ, Sweatt JD. Cognitive containing protein (LRPPRC) for anti- neuroepigenetics: a role for epigenetic apoptosis and tumourigenesis in cancers. mechanisms in learning and memory. Eur J Cancer. 2012;48(15):2462-73. Neurobiol Learn Mem. 2011;96(1):2-12.

69. Minati L, Edginton T, Bruzzone 72. Jankovic J. Parkinson's disease: MG, Giaccone G. Current concepts in clinical features and diagnosis. J Neurol Alzheimer's disease: a multidisciplinary Neurosurg Psychiatry. 2008;79(4):368-76. review. Am J Alzheimers Dis Other 73. Zimprich A, Biskup S, Leitner P, Demen. 2009;24(2):95-121. Lichtner P, Farrer M, Lincoln S, et al. 70. Hosp F, Vossfeldt H, Heinig M, Mutations in LRRK2 cause autosomal- Vasiljevic D, Arumughan A, Wyler E, et al. dominant parkinsonism with pleomorphic Quantitative interaction proteomics of pathology. Neuron. 2004;44(4):601-7. neurodegenerative disease proteins. Cell 74. Gaweda-Walerych K, Mohagheghi Rep. 2015;11(7):1134-46. F, Zekanowski C, Buratti E. Parkinson's 71. Acharya NK, Nagele EP, Han M, disease-related gene variants influence pre- Coretti NJ, DeMarshall C, Kosciuk MC, et mRNA splicing processes. Neurobiol al. Neuronal PAD4 expression and protein Aging. 2016;47:127-38. citrullination: possible role in production 75. Samii A, Nutt JG, Ransom BR. of autoantibodies associated with Parkinson's disease. Lancet. neurodegenerative disease. J Autoimmun. 2004;363(9423):1783-93. 2012;38(4):369-80.