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SURVEY and SUMMARY Novel Ribozymes: Discovery, Catalytic Mechanisms, and the Quest to Understand Biological Function Christina E

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SURVEY and SUMMARY Novel Ribozymes: Discovery, Catalytic Mechanisms, and the Quest to Understand Biological Function Christina E 9480–9494 Nucleic Acids Research, 2019, Vol. 47, No. 18 Published online 31 August 2019 doi: 10.1093/nar/gkz737 SURVEY AND SUMMARY Novel ribozymes: discovery, catalytic mechanisms, and the quest to understand biological function Christina E. Weinberg1,*, Zasha Weinberg 2,* and Christian Hammann3,* 1Institute for Biochemistry, Leipzig University, Bruderstraße¨ 34, 04103 Leipzig, Germany, 2Bioinformatics Group, Department of Computer Science and Interdisciplinary Centre for Bioinformatics, Leipzig University, Hartelstraße¨ 16–18, 04107 Leipzig, Germany and 3Ribogenetics & Biochemistry, Department of Life Sciences and Chemistry, Jacobs University Bremen gGmbH, Campus Ring 1, 28759 Bremen, Germany Received February 23, 2019; Revised August 08, 2019; Editorial Decision August 12, 2019; Accepted August 21, 2019 ABSTRACT INTRODUCTION Small endonucleolytic ribozymes promote the self- In the current year, we look back to 30 years of contin- cleavage of their own phosphodiester backbone at a ued discoveries on catalytic RNA, after the Nobel Prize specific linkage. The structures of and the reactions in Chemistry was awarded to Tom Cech and Sid Alt- catalysed by members of individual families have man in 1989 ‘for their discovery of catalytic properties been studied in great detail in the past decades. In of RNA’(http://www.nobelprize.org/prizes/chemistry/1989/ summary/). The distinguished discoveries were made on recent years, bioinformatics studies have uncovered self-splicing Group I introns (1) and on the RNA subunit a considerable number of new examples of known of bacterial RNase P (2). The reactions of both these cat- catalytic RNA motifs. Importantly, entirely novel ri- alytic RNAs target RNA 3,5-phosphodiester bonds, ei- bozyme classes were also discovered, for most of ther in a series of two autocatalytic transesterification re- which both structural and biochemical information actions in cis, or by means of a hydrolysis reaction car- became rapidly available. However, for the majority of ried out by the catalytic RNA component M1 of bacterial the new ribozymes, which are found in the genomes RNase P (Figure 1A, C). The majority of currently known natural ribozymes, short for ribonucleic acid enzymes, act of a variety of species, a biological function remains elusive. Here, we concentrate on the different ap- on RNA 3 ,5 -phosphodiester bonds, with further examples proaches to find catalytic RNA motifs in sequence being group II introns (3,4) and the small nucleolytic ri- databases. We summarize the emerging principles of bozymes (5), whose reactions are shown in Figure 1B, D. In contrast, the peptidyl transferase centre of the ribosome RNA catalysis as observed for small endonucleolytic consists of an RNA that catalyses the formation of peptide ribozymes. Finally, we address the biological func- bonds (6; Figure 1E). tions of those ribozymes, where relevant information Early observations made by Harry Noller et al. already is available and common themes on their cellular ac- pointed strongly towards the possibility that proteins are tivities are emerging. We conclude by speculating on made in an RNA-catalysed fashion, as translation proved to the possibility that the identification and characteri- be resistant to mild proteolytic treatment (7). Final proof for zation of proteins that we hypothesize to be endoge- ribosomal RNAs being the catalyst in protein formation, nously associated with catalytic RNA might help in rather than ribosomal proteins, came from high-resolution answering the ever-present question of the biologi- crystal structures that revealed that the peptidyl transferase cal function of the growing number of genomically centre is made up exclusively of RNA constituents (6,8). encoded, small endonucleolytic ribozymes. In all likelihood, RNA-catalysed reactions had a broader range of substrate classes during evolution; however, due to the greater chemical diversity of amino acid side chains, pro- teinaceous enzymes would take over in the transition from *To whom correspondence should be addressed. Christian Hammann. Tel: +49 421 200374; Fax: +49 421 200374; Email: [email protected] Correspondence may also be addressed to Zasha Weinberg. Tel: +49 341 971 6657; Fax: +49 341 9716679; Email: [email protected] Correspondence may also be addressed to Christina E. Weinberg. Tel: +49 341 973 6995; Fax: +49 341 973 6919; Email: [email protected] C The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected] Nucleic Acids Research, 2019, Vol. 47, No. 18 9481 Figure 1. Reactions naturally catalysed by RNA. Two sequential transesterification reactions catalysed by group I. (A) and group II (B) introns in cis. These result in joined exons and linear and lariat introns, respectively. RNA hydrolysis catalysed in trans by the M1 RNA subunit of bacterial RNase P. (C) results in a phosphate containing 5 end of the mature tRNA as the 3 cleavage product (3 P) and a 3 hydroxyl group at the 5 cleavage product (5 P). Small nucleolytic ribozymes undergo transesterification reactions in cis (D), in which a specific 2-hydroxyl attacks the neighbouring 3,5-phosphodiester bond. This results in a 2,3-cyclic phosphate and a 5 hydroxyl at the 5 and 3 cleavage products, respectively. (E) Peptide bond formation catalysed in the ribosomal peptidyl transferase centre. This figure was adapted from (163). 9482 Nucleic Acids Research, 2019, Vol. 47, No. 18 the RNA World (9) to the current protein-dominated life. observations that hepatitis ␦ virus (HDV) has similar prop- Such a shift in mode of operation is not easily conceivable erties to those of plant satellite RNAs spurred the identifi- for the peptidyl transferase centre in the ribosome and in- cation of the HDV ribozyme (Figure 3C; 18). Finally, the deed this most central reaction in the generation of proteins Varkud satellite (VS) ribozyme (Figure 3D) was found in remained RNA-catalysed. To make up for the limited chem- transcripts of DNA satellites associated with mitochondria ical variability of the RNA nucleobases, in comparison to in certain Neurospora isolates (19). proteins, the efficiency of the essential, non-replaceable pep- tidyl transferase reaction was improved by other means. Ex- amples of these improvements include not only the obvious DISCOVERY BY BIOINFORMATICS ribosomal and auxiliary proteins, but also the more than one hundred chemical modifications that are known to oc- The remaining self-cleaving ribozyme classes, among those cur in tRNA molecules (10). These modifications allow for currently known, were found bioinformatically. The glmS an optimized translation as a consequence of altered bind- ribozyme (Figure 3E) was uncovered in a search for novel ing energies between codon and anticodon, as highlighted classes of riboswitches (20). Riboswitches are RNAs that recently in a seminal contribution (11). While most tRNA regulate genes based on their ability to detect a specific small modifications are not absolutely essential, the absence ofin- molecule metabolite or ion ligand (21). Since riboswitches dividual chemical modifications on tRNAs can have dra- usually occur in the 5 UTRs of bacterial genes, the search matic effects on protein translation (12), which results in compared InterGenic Regions (IGRs) in the bacterium protein aggregation (13), further highlighting their impor- Bacillus subtilis against those of other Firmicute species. tance in and necessity for the optimization of the peptidyl Conserved IGRs upstream of metabolic genes were inves- transferase reaction. tigated further. The glmS ribozyme is found in the 5 UTRs By contrast, the four building blocks of RNA appear well of glmS mRNAs, whose product synthesizes glucosamine suited to catalyse reactions at 3,5-phosphodiester bonds, 6-phosphate (GlcN6P). The ribozyme cleaves itself only in often with the help of divalent metal ions and, occasionally, the presence of high concentrations of GlcN6P (14), and, in a small-molecule catalytic co-factor in the glmS ribozyme a negative feedback loop, this cleavage dramatically reduces (14, and see below). Beyond the self-splicing introns and gene expression of glmS (22). the M1 RNA mentioned above, an increasing number of Roughly 10 years later, a general search for all types of ribozyme classes catalysing cleavage reactions of phospho- conserved RNA structures in bacteria revealed the twister diester bonds was discovered in the past 30 years. Together, ribozyme (Figure 3F; (23). This search analysed multiple these RNA motifs form the family of the self-cleaving ri- lineages of bacteria and archaea (24). In brief, for each lin- bozymes, as they naturally cleave distinct positions in their eage, it grouped together similar IGRs based on BLAST own phosphodiester backbone (Figure 2). As the reaction (25) comparisons. For each group of similar IGRs, the pro- is reversible, the ribozymes can in principle also acceler- cess determined a possible secondary structure using the ate the reverse, ligation reaction (Figure 2). This is, how- CMfinder software (26) and automatically provided a score ever, observed only in some cases due to instability
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